3,4-Disubstituted, 3,5-disubstituted and 3,4,5-substituted piperidines

ABSTRACT

The invention relates to substituted piperidine, piperazine, morpholine and thiomorpholine compounds useful in the treatment of Alzheimer&#39;s disease and more specifically to compounds that are capable of inhibiting beta-secretase, an enzyme that cleaves amyloid precursor protein to produce amyloid beta peptide (A-beta), a major component of the amyloid plaques found in the brains of Alzheimer&#39;s sufferers.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The invention relates to substituted piperidine and piperazinecompounds useful in the treatment of Alzheimer's disease and morespecifically to compounds that are capable of inhibiting beta-secretase,an enzyme that cleaves amyloid precursor protein to produce amyloid betapeptide (A-beta), a major component of the amyloid plaques found in thebrains of Alzheimer's sufferers.

[0003] 2. Description of Related Art

[0004] Alzheimer's disease (AD) is a progressive degenerative disease ofthe brain primarily associated with aging. Clinical presentation of ADis characterized by loss of memory, cognition, reasoning, judgment, andorientation. As the disease progresses, motor, sensory, and linguisticabilities are also affected until there is global impairment of multiplecognitive functions. These cognitive losses occur gradually, buttypically lead to severe impairment and eventual death in the range offour to twelve years. Alzheimer's disease is characterized by two majorpathologic observations in the brain: neurofibrillary tangles and betaamyloid (or neuritic) plaques, comprised predominantly of an aggregateof a peptide fragment know as A-beta. Individuals with AD exhibitcharacteristic beta-amyloid deposits in the brain (beta amyloid plaques)and in cerebral blood vessels (beta amyloid angiopathy) as well asneurofibrillary tangles. Neurofibrillary tangles occur not only inAlzheimer's disease but also in other dementia-inducing disorders. Onautopsy, large numbers of these lesions are generally found in areas ofthe human brain important for memory and cognition.

[0005] Smaller numbers of these lesions in a more restricted anatomicaldistribution are found in the brains of most aged humans who do not haveclinical AD. Amyloidogenic plaques and vascular amyloid angiopathy alsocharacterize the brains of individuals with Trisomy 21 (Down'sSyndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-Type (HCHWA-D), and other neurodegenerative disorders.Beta-amyloid is a defining feature of AD, now believed to be a causativeprecursor or factor in the development of disease. Deposition of A-betain areas of the brain responsible for cognitive activities is a majorfactor in the development of AD. Beta-amyloid plaques are predominantlycomposed of amyloid beta peptide (A-beta, also sometimes designatedbetaA4). A-beta peptide is derived by proteolysis of the amyloidprecursor protein (APP) and is comprised of 39-42 amino acids. Severalproteases called secretases are involved in the processing of APP.

[0006] Cleavage of APP at the N-terminus of the A-beta peptide bybeta-secretase and at the C-terminus by the gamma-secretase complexconstitutes the beta-amyloidogenic pathway, i.e. the pathway by whichA-beta is formed. Cleavage of APP by alpha-secretase producesalpha-sAPP, a secreted form of APP that does not result in beta-amyloidplaque formation. This alternate pathway precludes the formation ofA-beta peptide. A description of the proteolytic processing fragments ofAPP is found, for example, in U.S. Pat. Nos. 5,441,870; 5,721,130; and5,942,400.

[0007] An aspartyl protease has been identified as the enzymeresponsible for processing of APP at the beta-secretase cleavage site.The beta-secretase enzyme has been disclosed using varied nomenclature,including BACE, Asp, and Memapsin. See, for example, Sindha et al.,1999, Nature 402:537-554 (p501) and published PCT applicationWO00/17369.

[0008] Several lines of evidence indicate that progressive cerebraldeposition of beta-amyloid peptide (A-beta) plays a seminal role in thepathogenesis of AD and can precede cognitive symptoms by years ordecades. See, for example, Selkoe, 1991, Neuron 6:487. Release of A-betafrom neuronal cells grown in culture and the presence of A-beta incerebrospinal fluid (CSF) of both normal individuals and AD patients hasbeen demonstrated. See, for example, Seubert et al., 1992, Nature359:325-327.

[0009] It has been proposed that A-beta peptide accumulates as a resultof APP processing by beta-secretase, thus inhibition of this enzyme'sactivity is desirable for the treatment of AD. In vivo processing of APPat the beta-secretase cleavage site is thought to be a rate-limitingstep in A-beta production, and is thus a therapeutic target for thetreatment of AD. See for example, Sabbagh, M., et al., 1997, Alz. Dis.Rev. 3, 1-19.

[0010] BACE1 knockout mice fail to produce A-beta, and present a normalphenotype. When crossed with transgenic mice that over express APP, theprogeny show reduced amounts of A-beta in brain extracts as comparedwith control animals (Luo et al., 2001 Nature Neuroscience 4:231-232).This evidence further supports the proposal that inhibition ofbeta-secretase activity and reduction of A-beta in the brain provides atherapeutic method for the treatment of AD and other beta amyloiddisorders.

[0011] At present there are no effective treatments for halting,preventing, or reversing the progression of Alzheimer's disease.Therefore, there is an urgent need for pharmaceutical agents capable ofslowing the progression of Alzheimer's disease and/or preventing it inthe first place.

[0012] Compounds that are effective inhibitors of beta-secretase, thatinhibit beta-secretase-mediated cleavage of APP, that are effectiveinhibitors of A-beta production, and/or are effective to reduce amyloidbeta deposits or plaques, are needed for the treatment and prevention ofdisease characterized by amyloid beta deposits or plaques, such as AD.

SUMMARY OF THE INVENTION

[0013] The invention encompasses the substituted piperidine andpiperazine compounds of the formulas shown below, pharmaceuticalcompositions containing the compounds and methods employing suchcompounds or compositions in the treatment of Alzheimer's disease andmore specifically compounds that are capable of inhibitingbeta-secretase, an enzyme that cleaves amyloid precursor protein toproduce A-beta peptide, a major component of the amyloid plaques foundin the brains of Alzheimer's sufferers.

[0014] In one aspect, the invention provides compounds of the formula I:

[0015] or a pharmaceutically acceptable salt or ester thereof,

[0016] wherein Z is CH or N;

[0017] wherein R₁ and R₃ are independently:

[0018] (I) C₁-C₁₀ alkyl, optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, —O-phenyl,—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are independently —H or C₁-C₆alkyl, —OC═O NR_(1-a)R_(1-b), —S(═O)₂ R_(1-a), —NR_(1-a)C═ONR_(1-a)R_(1-b), —C═O NR_(1-a)R_(1-b), and —S(═O)₂ NR_(1-a)R_(1-b),(CH₂)₀-3—(C₃-C₈) cycloalkyl where cycloalkyl can be optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆alkoxy, —O-phenyl, —CO—OH, —CO—O—(C₁-C₄ alkyl), —NR_(1-a)R_(1-b); C₁-C₃alkoxy-(R_(1-aryl)) , C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0019] (II) —(CH₂)_(n1)-(R_(1-aryl)) where n₁ is zero or one and whereR_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl and indanyl, indenyl,dihydronaphthyl, tetralinyl optionally substituted with one, two, threeor four of the following independently selected substituents on the arylring:

[0020] (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —NR_(1-a)R_(1-b), —C—N, —CF₃, C₁-C₃ alkoxy,C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0021] (2) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl),—S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl),—S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl),—SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl), —C≡N, —CF₃, C₁-C₃alkoxy, —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0022] (3) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl),—S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl),—S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl),—SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₃alkoxy, —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0023] (4) —F, Cl, —Br and —I,

[0024] (5) —C₁-C₆ alkoxy optionally substituted with one, two or three—F,

[0025] (6) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as definedbelow,

[0026] (7) —OH,

[0027] (8) —C≡N,

[0028] (9) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —Br,—I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆alkyl), —SO₂(C₁₋₆ alkyl), —S° 2 (aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆alkyl), —C—N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0029] (10) —CO—(C₁-C₄ alkyl),

[0030] (11) —SO₂—NR_(1-a)R_(1-b),

[0031] (12) —CO—NR_(1-a)R_(1-b),

[0032] (13) —SO₂— (C₁-C₄ alkyl),

[0033] (III) —(CH₂)_(n1)-(R_(1-heteroaryl)) where n₁ is as defined aboveand where R_(1-heteroaryl) is selected from the group consisting of:

[0034] pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl,indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benz imidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl,isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl,isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide,

[0035] where the R_(1-heteroaryl) group is bonded to —(CH₂)_(n1)— by anyring atom of the parent R_(1-heteroaryl) group substituted by hydrogensuch that the new bond to the R_(1-heteroaryl) group replaces thehydrogen atom and its bond, where heteroaryl is optionally substitutedwith one, two, three or four of:

[0036] (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —NR_(1-a)R_(1-b), —C—N, —CF₃, C₁-C₃ alkoxy,C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0037] (2) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl),—S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl),—S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl),—SO₂(aryl-C₁-6 alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₃alkoxy, —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0038] (3) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl),—S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl),—S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl),—SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₃alkoxy, —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0039] (4) —F, —Cl, —Br and —I,

[0040] (5) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[0041] (6) —NR_(N-2)R_(N-3),

[0042] (7) —OH,

[0043] (8) —C≡N,

[0044] (9) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents independently selected from the group consisting of—F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁-6 alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b),C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0045] (10) —CO— (C₁-C₄ alkyl),

[0046] (11) —SO₂—NR_(1-a)R_(1-b),

[0047] (12) —CO—NR_(1-a)R_(1-b),

[0048] (13) —SO₂— (C₁-C₄ alkyl), with the proviso that when n₁ is zero,R_(1-heteroaryl) is not bonded to the carbon chain by nitrogen,

[0049] (IV) —(CH₂)_(n1)— (R_(1-heterocycle)) where n, is as definedabove and R_(1-heterocycle) is selected from the group consisting of:

[0050] morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl,pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl,tetrahydrothienyl, homopiperidinyl, homomorpholinyl,homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl dihydropyrazinyl dihydropyridinyldihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienylS-oxide, tetrahydrothienyl S,S-dioxide, homothiomorpholinyl S-oxide,

[0051] where the R_(1-heterocycle) group is bonded by any atom of theparent R_(1-heterocycle) group substituted by hydrogen such that the newbond to the R_(1-heterocycle) group replaces the hydrogen atom and itsbond, where heterocycle is optionally substituted with one, two, threeor four:

[0052] (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —NR_(1-a)R_(1-b), —C≡N, —CF₃, C₁-C₃ alkoxy,C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R₁-heteroaryl),

[0053] (2) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl),—S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl),—S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl),—SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₃alkoxy, —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0054] (3) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —Br, —I, —OH—SH, —S(C₁₋₆ alkyl),—S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl),—S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl),—SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₃alkoxy, —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0055] (4) —F, —Cl, —Br and —I,

[0056] (5) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[0057] (6) —NR_(N-2)R_(N-3),

[0058] (7) —OH,

[0059] (8) —C=_N,

[0060] (9) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —Br,—I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₆alkyl), —C—N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0061] (10) —CO— (C₁-C₄ alkyl),

[0062] (11) —SO₂—NR_(1-a)R_(1-b),

[0063] (12) —CO—NR_(1-a)R_(1-b),

[0064] (13) —SO₂— (C₁-C₄ alkyl),

[0065] (14) ═O, with the proviso that when n, is zero R_(1-heterocycle)is not bonded to the carbon chain by nitrogen;

[0066] (V) —H;

[0067] (VI) R_(N-)1-X_(N)— where X_(N) is selected from the groupconsisting of:

[0068] (A) —CO—,

[0069] (B) —SO₂

[0070] where R_(N-1) is selected from the group consisting of:

[0071] (A) R_(N-aryl) where R_(N-aryl) is phenyl, 1-naphthyl,2-naphthyl, tetralinyl, indanyl, dihydronaphthyl or6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, optionally substituted withone, two or three of the following substituents which can be the same ordifferent and are:

[0072] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b),C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0073] (2) —OH,

[0074] (3) —NO₂,

[0075] (4) —F, —Cl, —Br, —I,

[0076] (5) —CO—OH,

[0077] (6) —C≡N,

[0078] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) arethe same or different and are selected from the group consisting of:

[0079] (a) —H,

[0080] (b) —C₁-C₆ alkyl optionally substituted with one substitutentselected from the group consisting of:

[0081]  (i) —OH,

[0082]  (ii) —NH₂,

[0083] (c) —C₁-C₆ alkyl optionally substituted with one to three groupsindependently selected from —F, —Cl, —Br, and —I,

[0084] (d) —C₃-C₇ cycloalkyl,

[0085] (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[0086] (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),

[0087] (g) —C₂-C₆ alkenyl with one or two double bonds,

[0088] (h) —C₂-C₆ alkynyl with one or two triple bonds,

[0089] (i) —C₁-C₆ hydrocarbyl chain with one double bond and one triplebond,

[0090] (j) —R_(1-aryl),

[0091] (k) —R_(1-heteroaryl),

[0092] (8) —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),

[0093] (9) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one, two or three doublebonds),

[0094] (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one, two or three triplebonds),

[0095] (11) —(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl),

[0096] (12) —(CH₂)₀₋₄-CO—R_(1-aryl),

[0097] (13) —(CH₂)₀₋₄-CO—R_(1-heteroaryl),

[0098] (14) —(CH₂)₀₋₄-CO—R_(1-heterocycle),

[0099] (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from thegroup consisting of morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinylwhere each group is optionally substituted with one, two, three, or fourof C₁-C₆ alkyl,

[0100] (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from thegroup consisting of:

[0101] (a) C₁-C₆ alkyl,

[0102] (b) —(CH₂)₀₋₂—(R_(1-aryl)),

[0103] (c) C₂-C₆ alkenyl containing one or two double bonds,

[0104] (d) C₂-C₆ alkynyl containing one or two triple bonds,

[0105] (e) C₃-C₇ cycloalkyl,

[0106] (f) —(CH₂)₀₋₂-(R_(1-heteroaryl)),

[0107] (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[0108] (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl),

[0109] (19) —(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl),

[0110] (20) —(CH₂)₀₋₄—SO₂-(C₃-C₇ cycloalkyl),

[0111] (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can bethe same or different,

[0112] (22) —(CH₂)₀₋₄—N(H or R_(N-5)) —CO—N(R_(N-5))₂, where eachR_(N-5) is independently defined herein,

[0113] (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where each R_(N-5) isindependently defined herein,

[0114] (24) —(CH₂)₀₋₄—N(—H or R_(N-5)) —CO—R_(N-2),

[0115] (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[0116] (26) —(CH₂)₀₋₄—R_(N-4),

[0117] (27) —(CH₂)₀₋₄—O—CO— (C₁-C₆ alkyl),

[0118] (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-1))₂ where R_(N-1) is —H or C₁-C₄alkyl,

[0119] (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[0120] (30) —(CH₂)₀₋₄-O—CS—N(R_(N-5))₂,

[0121] (31) —(CH₂)₀₋₄—O— (R_(N-5))₂,

[0122] (32) —(CH₂)₀₋₄—O— (R_(N-5))₂—COOH,

[0123] (33) —(CH₂)₀₋₄—S—(R_(N-5))₂,

[0124] (34) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with one,two, three, four, or five of —F),

[0125] (35) C₃-C₇ cycloalkyl,

[0126] (36) C₂-C₆ alkenyl having one or two double bonds and which isoptionally substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,—S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl),—S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl),—SO₂ (C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl),—C—N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)),C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0127] (37) C₂-C₆ alkynyl with one or two triple bonds optionallysubstituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆alkyl), —S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆alkyl), —S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆alkyl), —SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃,C₁-C₃ alkoxy, —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0128] (38) —(CH₂)₀₋₄—N(—H or R_(N-5)) —SO₂—R_(N-2), or

[0129] (39) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,

[0130] (B) —R_(N-heteroaryl) where R_(N-heteroaryl) carries the samedefinition as R_(1-heteroaryl), where the R_(N-heteroaryl) group isbonded by any atom of the parent R_(N-heteroaryl) group substituted byhydrogen such that the new bond to the R_(N-heteroaryl) group replacesthe hydrogen atom and its bond, where heteroaryl is optionallysubstituted with one, two, three, or four groups independently selectedfrom:

[0131] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂ (C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —C═N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)) C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0132] (2) —OH,

[0133] (3) —NO₂,

[0134] (4) —F, —Cl, —Br, —I,

[0135] (5) —CO—OH,

[0136] (6) —C—N,

[0137] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[0138] (C) R_(N-aryl)-W—R_(N-aryl),

[0139] (D) R_(N-aryl)-W—R_(N-heteroaryl),

[0140] (E) R_(N-aryl)-W—R_(N-heterocycle), where R_(N-heterocycle) isthe same as R_(N-heterocycle),

[0141] (F) R_(N-heteroaryl)-W—R_(N-aryl),

[0142] (G) R_(N-heteroaryl)-W—R_(N-heteroaryl),

[0143] (H) R_(N-heteroaryl)-W—R_(N-heterocycle),

[0144] (I) R_(N-heterocycle)-W—R_(N-aryl),

[0145] (J) R_(N-heterocycle)-W—R_(N-heteroaryl),

[0146] (K) R_(N-heterocycle)-W—R_(N-heterocycle), and

[0147] where W is

[0148] (1) —(CH₂)₀₋₄—,

[0149] (2) —O—,

[0150] (3) —S(O)₀₋₂—,

[0151] (4) —N(R_(N-5))—, or

[0152] (5) —CO—;

[0153] (VII) —(CR_(C-x)R_(C-y))₀₋₄R_(C-aryl) where R_(C-x) and R_(C-y)are —H,

[0154] C₁-C₄ alkyl optionally substituted with one or two —OH,

[0155] C₁-C₄ alkoxy optionally substituted with one, two, or three of

[0156] —F,

[0157] —(CH₂)₀₋₄—C₃-C₇ Cycloalkyl,

[0158] C₂-C₆ alkenyl containing one or two double bonds,

[0159] C₂-C₆ alkynyl containing one or two triple bonds,

[0160] phenyl,

[0161]  and where R_(C-x) and R_(C-y) are taken together with the carbonto which they are attached to form a carbocycle of three, four, five,six and seven carbon atoms, optionally where one carbon atom is replacedby a heteroatom selected from the group consisting of —O—, —S—, —SO₂—,—NR_(N-2)— and R_(C-aryl) is the same as RN-aryl;

[0162] (VIII) —(CR_(C-x)R_(C-y))₀₋₄-R_(C-aryl)-R_(C-aryl),

[0163] (IX) —(CR_(C-x)R_(C-y))₀₋₄-R_(C-aryl)-R_(C-heteroary),

[0164] (X) —(CR_(C-x)R_(C-y))₀₋₄-R_(C-heteroaryl)-R_(C-aryl),

[0165] (XI) —(CR_(C-x)R_(C-y))-4-R_(C-heteroaryl)-R_(C-heteroaryl)), (

[0166] XII) —(CR_(C-x)R_(C-y))₀₋₄-R_(C-aryl)-R_(C-heterocycle and R)_(C-heterocycle is the same as RN-heterocycle,)

[0167] (XIII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl-R) _(C-heterocycle,)

[0168] (XIV) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle-R) _(C-aryl,)

[0169] (XV) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle-R) _(C-heteroaryl)

[0170] (XVI) —(CR_(C-x)R_(C-y))₀₋₄-R_(C-heterocycle-R)_(C-heterocycle (XVII) -[C(Rc-) ₁) (Rc-2)] l-₃—CO—N— (Rc-3)₂ where Rc-1and Rc-2 are the same or different and are selected from the groupconsisting of: (A) —H,

[0171] (B) —C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0172] (C) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl),—S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl),—S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl),—SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₆alkoxy, —O-phenyl, —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0173] (D) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with one,two or three substituents selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0174] (E) —(C₁-C₄ alkyl)-R_(C′-aryl) where R_(C′-aryl) is as definedfor R_(C′-aryl),

[0175] (F) —(C₁-C₄ alkyl)-R_(C-heteroaryl),

[0176] (G) —(C₁-C₄ alkyl)-R_(C-heterocycle),

[0177] (H) —R_(C-heteroaryl),

[0178] (I) —R_(C-heterocycle), and

[0179] (J) —R_(C′-aryl),

[0180] and where R_(C-3) is the same or different and is:

[0181] (A) —H,

[0182] (B) —C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0183] (C) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,

[0184] (D) —(C₁-C₄ alkyl)-R_(C′-aryl),

[0185] (E) —(C₁-C₄ alkyl) -R_(C-heteroaryl), or

[0186] (F) —(C₁-C₄ alkyl)-R_(C-heterocycle);

[0187] (XVIII) —(CH₂)_(o)-Q-(CH₂)_(p)—B, where o and p are independentlyintegers of 1-4, Q is O, S, SO, SO₂, NR₁, and B is C₁₋₀₆ alkyl, aryl,heteroaryl, or heterocycle;

[0188] (XIX) —O—R₉, —S—R₉, —NH—R₉, or N(R₉)₂;

[0189] (XX) —OC(═O)—R₉

[0190] (XXI) —C(═O)O—R₉

[0191] (XXII) —N(R₈)C(═O) —R₉

[0192] (XXIII) —C(═O)N(R₈)—R₉

[0193] (XXIV) —SO₂N(R₈)C(═O) —R₉

[0194] (XXV) —C(═O)N(R₈)SO₂—R₉

[0195] (XXVI) —SO₂—R₉;

[0196] wherein R₈ is defined as H or C₁-C₆ alkyl optionally substitutedwith one to three groups independently selected from —OH, —NH₂, —F, —Cl,—Br, and —I;

[0197] wherein R₉ is defined as (I)—(XVIII) above

[0198] and wherein R₂ is is C₁ to C₆ alkyl , cyclohexyl, cyclopentyl,pyridinyl, phenyl, isoxazole, pyrazole, furan, thiophene, and other fiveand six membered heterocycles containing carbon, nitrogen, oxygen andsulfur, said C₁ to C₆ alkyl, cyclohexyl, cyclopentyl, pyridinyl, phenyl,furan, thiophene may be optionally substituted with one, two or threeradicals selected from CF₃, OCF₃, hydroxyl, halo, C₁₋₂-alkyl,C₁₋₂-haloalkyl, cyano, carboxyl, C₁₋₂-alkoxycarbonyl, C₁₋₂-hydroxyalkyl,thioalkyl, aminosulfonyl, C₁₋₂-alkylaminosulfonyl, methylC₁₋₂-haloalkoxy, amino, C₁₋₂-alkylamino, phenylamino, nitro,C₁₋₂-alkoxy-C₁₋₂-alkyl, C₁₋₂-alkylsulfinyl, C₁₋₂-alkoxy andC₁₋₃-alkylthio.

[0199] In another aspect of the invention, at least one of R₁, R₂ or R₃is H; in a further embodiment, at least two of R₁, R₂ or R₃ is H.

[0200] The invention also includes a method of treating a patient whohas, or in preventing a patient from getting, a disease or conditionselected from the group consisting of Alzheimer's disease, for helpingprevent or delay the onset of Alzheimer's disease, for treating patientswith mild cognitive impairment (MCI) and preventing or delaying theonset of Alzheimer's disease in those who would progress from MCI to AD,for treating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobar hemorrhages, for treating otherdegenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, or diffuse Lewy body typeof Alzheimer's disease and who is in need of such treatment whichincludes administration of a therapeutically effective amount of acompound of formula I.

[0201] In an embodiment, this method of treatment can be used where thedisease is Alzheimer's disease.

[0202] In an embodiment, this method of treatment can help prevent ordelay the onset of Alzheimer's disease.

[0203] In an embodiment, this method of treatment can be used where thedisease is mild cognitive impairment.

[0204] In an embodiment, this method of treatment can be used where thedisease is Down's syndrome.

[0205] In an embodiment, this method of treatment can be used where thedisease is Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-Type.

[0206] In an embodiment, this method of treatment can be used where thedisease is cerebral amyloid angiopathy.

[0207] In an embodiment, this method of treatment can be used where thedisease is degenerative dementias.

[0208] In an embodiment, this method of treatment can be used where thedisease is diffuse Lewy body type of Alzheimer's disease.

[0209] In an embodiment, this method of treatment can treat an existingdisease, such as those listed above.

[0210] In an embodiment, this method of treatment can prevent a disease,such as those listed above, from developing.

[0211] In an embodiment, this method of treatment can employtherapeutically effective amounts: for oral administration from about0.1 mg/day to about 3,000, preferably about 1,000 mg/day; forparenteral, sublingual, intranasal, intrathecal administration fromabout 0.5 to about 500 mg/day, preferably about 100 mg/day; for depoadministration and implants from about 0.5 mg/day to about 50 mg/day;for topical administration from about 0.5 mg/day to about 200 mg/day;for rectal administration from about 0.5 mg to about 500 mg.

[0212] In an embodiment, this method of treatment can employtherapeutically effective amounts: for oral administration from about 1mg/day to about 100 mg/day; and for parenteral administration from about5 to about 50 mg daily.

[0213] In an embodiment, this method of treatment can employtherapeutically effective amounts for oral administration from about 5mg/day to about 50 mg/day.

[0214] The invention also includes a pharmaceutical composition whichincludes a compound of formula I or a pharmaceutically acceptable saltor ester thereof; and an inert diluent or edible carrier.

[0215] The invention also includes the use of a compound of formula I ora pharmaceutically acceptable salt or ester thereof for the manufactureof a medicament for use in treating a patient who has, or in preventinga patient from getting, a disease or condition selected from the groupconsisting of Alzheimer's disease, for helping prevent or delay theonset of Alzheimer's disease, for treating patients with mild cognitiveimpairment (MCI) and preventing or delaying the onset of Alzheimer'sdisease in those who would progress from MCI to AD, for treating Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, diffuse Lewy body type of Alzheimer's disease and who isin need of such treatment.

[0216] In an embodiment, this use of a compound of formula (I) can beemployed where the disease is Alzheimer's disease.

[0217] In an embodiment, this use of a compound of formula (I) can helpprevent or delay the onset of Alzheimer's disease.

[0218] In an embodiment, this use of a compound of formula (I) can beemployed where the disease is mild cognitive impairment.

[0219] In an embodiment, this use of a compound of formula (I) can beemployed where the disease is Down's syndrome.

[0220] In an embodiment, this use of a compound of formula (I) can beemployed where the disease is Hereditary Cerebral Hemorrhage withAmyloidosis of the Dutch-Type.

[0221] In an embodiment, this use of a compound of formula (I) can beemployed where the disease is cerebral amyloid angiopathy.

[0222] In an embodiment, this use of a compound of formula (I) can beemployed where the disease is degenerative dementias.

[0223] In an embodiment, this use of a compound of formula (I) can beemployed where the disease is diffuse Lewy body type of Alzheimer'sdisease.

[0224] In an embodiment, this use of a compound of formula (I) employs apharmaceutically acceptable salt selected from the group consisting ofsalts of the following acids hydrochloric, hydrobromic, hydroiodic,nitric, sulfuric, phosphoric, citric, methanesulfonic, CH₃—(CH₂) —COOHwhere n is 0 thru 4, HOOC—(CH₂)_(n)—COOH where n is as defined above,HOOC—CH═CH—COOH, and phenyl-COOH.

[0225] The invention also includes methods for inhibiting beta-secretaseactivity, for inhibiting cleavage of amyloid precursor protein (APP), ina reaction mixture, at a site between Met596 and Asp597, numbered forthe APP-695 amino acid isotype, or at a corresponding site of an isotypeor mutant thereof; for inhibiting production of amyloid beta peptide (Abeta) in a cell; for inhibiting the production of beta-amyloid plaque inan animal; and for treating or preventing a disease characterized bybeta-amyloid deposits in the brain. These methods each includeadministration of a therapeutically effective amount of a compound offormula I or a pharmaceutically acceptable salt or ester thereof.

[0226] The invention also includes a method for inhibitingbeta-secretase activity, including exposing said beta-secretase to aneffective inhibitory amount of a compound of formula I or apharmaceutically acceptable salt or ester thereof.

[0227] In an embodiment, this method includes exposing saidbeta-secretase to said compound in vitro.

[0228] In an embodiment, this method includes exposing saidbeta-secretase to said compound in a cell.

[0229] In an embodiment, this method includes exposing saidbeta-secretase to said compound in a cell in an animal.

[0230] In an embodiment, this method includes exposing saidbeta-secretase to said compound in a human.

[0231] The invention also includes a method for inhibiting cleavage ofamyloid precursor protein (APP), in a reaction mixture, at a sitebetween Met596 and Asp597, numbered for the APP-695 amino acid isotype;or at a corresponding site of an isotype or mutant thereof, includingexposing said reaction mixture to an effective inhibitory amount of acompound of formula I or a pharmaceutically acceptable salt or esterthereof.

[0232] In an embodiment, this method employs a cleavage site: betweenMet652 and Asp653, numbered for the APP-751 isotype; between Met 671 andAsp 672, numbered for the APP-770 isotype; between Leu596 and Asp597 ofthe APP-695 Swedish Mutation; between Leu652 and Asp653 of the APP-751Swedish Mutation; or between Leu671 and Asp672 of the APP-770 SwedishMutation.

[0233] In an embodiment, this method exposes said reaction mixture invitro.

[0234] In an embodiment, this method exposes said reaction mixture in acell.

[0235] In an embodiment, this method exposes said reaction mixture in ananimal cell.

[0236] In an embodiment, this method exposes said reaction mixture in ahuman cell.

[0237] The invention also includes a method for inhibiting production ofamyloid beta peptide (A beta) in a cell, including administering to saidcell an effective inhibitory amount of a compound of formula I or apharmaceutically acceptable salt or ester thereof.

[0238] In an embodiment, this method includes administering to ananimal.

[0239] In an embodiment, this method includes administering to a human.

[0240] The invention also includes a method for inhibiting theproduction of beta-amyloid plaque in an animal, including administeringto said animal an effective inhibitory amount of a compound of formula Ior a pharmaceutically acceptable salt or ester thereof.

[0241] In an embodiment, this method includes administering to a human.

[0242] The invention also includes a method for treating or preventing adisease characterized by beta-amyloid deposits in the brain includingadministering to a patient an effective therapeutic amount of a compoundof formula I or a pharmaceutically acceptable salt or ester thereof.

[0243] In an embodiment, this method employs a compound at a therapeuticamount in the range of from about 0.1 to about 1000 mg/day.

[0244] In an embodiment, this method employs a compound at a therapeuticamount in the range of from about 15 to about 1500 mg/day.

[0245] In an embodiment, this method employs a compound at a therapeuticamount in the range of from about 1 to about 100 mg/day.

[0246] In an embodiment, this method employs a compound at a therapeuticamount in the range of from about 5 to about 50 mg/day.

[0247] In an embodiment, this method can be used where said disease isAlzheimer's disease.

[0248] In an embodiment, this method can be used where said disease isMild Cognitive Impairment, Down's Syndrome, or Hereditary CerebralHemorrhage with Amyloidosis of the Dutch Type.

[0249] The invention also includes a composition includingbeta-secretase complexed with a compound of formula I or apharmaceutically acceptable salt or ester thereof.

[0250] The invention also includes a method for producing abeta-secretase complex including exposing beta-secretase to a compoundof formula I or a pharmaceutically acceptable salt or ester thereof, ina reaction mixture under conditions suitable for the production of saidcomplex.

[0251] In an embodiment, this method employs exposing in vitro.

[0252] In an embodiment, this method employs a reaction mixture that isa cell.

[0253] The invention also includes a component kit including componentparts capable of being assembled, in which at least one component partincludes a compound of formula (I) enclosed in a container.

[0254] In an embodiment, this component kit includes lyophilizedcompound, and at least one further component part includes a diluent.

[0255] The invention also includes a container kit including a pluralityof containers, each container including one or more unit dose of acompound of formula I or a pharmaceutically acceptable salt or esterthereof.

[0256] In an embodiment, this container kit includes each containeradapted for oral delivery and includes a tablet, gel, or capsule.

[0257] In an embodiment, this container kit includes each containeradapted for parenteral delivery and includes a depot product, syringe,ampoule, or vial.

[0258] In an embodiment, this container kit includes each containeradapted for topical delivery and includes a patch, medipad, ointment, orcream.

[0259] The invention also includes an agent kit including a compound offormula I or a pharmaceutically acceptable salt or ester thereof; andone or more therapeutic agents selected from the group consisting of anantioxidant, an anti-inflammatory, a gamma secretase inhibitor, aneurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an Abeta peptide, and an anti-A beta antibody.

[0260] The invention also includes a composition including: a compoundof formula I or a pharmaceutically acceptable salt or ester thereof; andan inert diluent or edible carrier.

[0261] In an embodiment, this composition includes a carrier that is anoil.

[0262] The invention also includes a composition including: a compoundof formula I or a pharmaceutically acceptable salt or ester thereof; anda binder, excipient, disintegrating agent, lubricant, or gildant.

[0263] The invention also includes a composition including: a compoundof formula I or a pharmaceutically acceptable salt ester thereof;disposed in a cream, ointment, or patch.

[0264] The invention provides compounds, compositions, kits, and methodsfor inhibiting beta-secretase-mediated cleavage of amyloid precursorprotein (APP). More particularly, the compounds, compositions, andmethods of the invention are effective to inhibit the production of Abeta peptide and to treat or prevent any human or veterinary disease orcondition associated with a pathological form of A beta peptide.

[0265] The compounds, compositions, and methods of the invention areuseful for treating humans who have Alzheimer's Disease (AD), forhelping prevent or delay the onset of AD, for treating patients withmild cognitive impairment (MCI), and preventing or delaying the onset ofAD in those patients who would otherwise be expected to progress fromMCI to AD, for treating Down's syndrome, for treating HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch Type, for treatingcerebral beta-amyloid angiopathy and preventing its potentialconsequences such as single and recurrent lobar hemorrhages, fortreating other degenerative dementias, including dementias of mixedvascular and degenerative origin, for treating dementia associated withParkinson's disease, dementia associated with progressive supranuclearpalsy, dementia associated with cortical basal degeneration, and diffuseLewy body type AD.

[0266] The compounds of the invention possess beta-secretase inhibitoryactivity. The inhibitory activities of the compounds of the inventionare readily demonstrated, for example, using one or more of the assaysdescribed herein or known in the art.

[0267] The invention includes a method for treating a patient who has,or in preventing a patient from getting, a disease or condition selectedfrom the group consisting of Alzheimer's disease, for helping prevent ordelay the onset of Alzheimer's disease, for treating patients with mildcognitive impairment (MCI) and preventing or delaying the onset ofAlzheimer's disease in those who would progress from MCI to AD, fortreating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobar hemorrhages, for treating otherdegenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, or diffuse Lewy body typeof Alzheimer's disease and who is in need of such treatment, comprisingadministering to such patient a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt or esterthereof, wherein Z, R₁, R₂ and R₃ are as defined above and below.

[0268] The invention further encompasses a method for making a compoundof formula (I), or a pharmaceutically acceptable salt or ester thereof,wherein Z, R₁, R₂ and R₃ are as defined as above or below.

DETAILED DESCRIPTION OF THE INVENTION

[0269] The invention relates to compounds of formula I, or apharmaceutically acceptable salt or ester thereof. The inventionencompasses all steroisomers of formula I and of the other compoundsdisclosed herein.

[0270] Further in accordance with the embodiment of the inventiondescribed above, compounds of Formula I include those where R₁ and R₃are independently:

[0271] (I) —(CH₂)_(n1)-(R_(1-aryl)), where n₁ is zero or one and whereR_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl,dihydronaphthalyl, or tetralinyl optionally substituted with one, two,three, or four of the following substituents on the aryl ring:

[0272] (A) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0273] (B) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0274] (C) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0275] (D) —F, Cl, —Br, or —I,

[0276] (E) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[0277] (F) —NR_(N-2)R_(N-3), where R_(N-2) and R_(N-3) are independentlyselected from the group consisting of:

[0278] (1) —H,

[0279] (2) —C₁-C₆ alkyl optionally substituted with one substituentselected from the group consisting of:

[0280] (a) —OH, and

[0281] (b) —NH₂,

[0282] (3) —C₁-C₆ alkyl optionally substituted with one to three —F,—Cl, —Br, or —I,

[0283] (4) —C₃-C₇ cycloalkyl,

[0284] (5) —(C₁-C₂ alkyl)—(C₃-C₇ cycloalkyl),

[0285] (6) —(C₁-C₆ alkyl) —O— (C₁-C₃ alkyl),

[0286] (7) —C₂-C₆ alkenyl with one or two double bonds,

[0287] (8) —C₂-C₆ alkynyl with one or two triple bonds,

[0288] (9) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[0289] (10) —R_(1-aryl), where R_(1-aryl) is as defined above, and

[0290] (11) —R_(1-heteroaryl),

[0291] (G) —OH,

[0292] (H)—C≡N

[0293] (I) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —Br,—I, —OH, —SH, —C—N, —CF₃, —NR_(1-a)R_(1-b), C₁-C₃ alkoxy, C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0294] (K) —CO—(C₁-C₄ alkyl),

[0295] (L) —SO₂—NR_(1-a)R_(1-b),

[0296] (M) —CO—NR_(1-a)R_(1-b), or

[0297] (N) —SO₂— (C₁-C₄ alkyl), or

[0298] (II) —(CH₂)_(n1)-(R_(1-heteroaryl)), where n₁ is zero or one andwhere R_(1-heteroaryl) is selected from the group consisting of:

[0299] pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl,indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl,

[0300] where the R_(1-heteroaryl) group is bonded to —(CH₂)_(n1)— by anyring atom of the parent R_(1-heteroaryl) group substituted by hydrogensuch that the new bond to the R_(1-heteroaryl) group replaces thehydrogen atom and its bond, where heteroaryl is optionally substitutedwith one, two, three, or four of:

[0301] (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy, C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0302] (2) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —SH, —CO—N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, C₁-C₃alkoxy, C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0303] (3) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, C₁-C₃alkoxy, C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0304] (4) —F, Cl, —Br, or —I, (5) —C₁-C₆ alkoxy optionally substitutedwith one, two, or three —F, (6) —NR_(N-2)R_(N-3),

[0305] (7) —OH,

[0306] (8) —C≡N,

[0307] (9) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —Br,—I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), whereR_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0308] (10) —CO— (C₁-C₄ alkyl),

[0309] (11) —SO₂—NR_(1-a)R_(1-b),

[0310] (12) —CO—NR_(1-a)R_(1-b), or

[0311] (13) —SO₂—(C₁-C₄ alkyl), with the proviso that when n_(i) is zeroR_(1-heteroaryl) is not bonded to the carbon chain by nitrogen.

[0312] In another embodiment, R₁ and R₃ are independently:

[0313] phenyl, 1-naphthyl, 2-naphthyl, tetralinyl, indanyl,dihydronaphthyl or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, each ofwhich is optionally substituted with one, two or three of the followingsubstituents which can be the same or different and are:

[0314] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0315] (2) —OH,

[0316] (3) —NO₂,

[0317] (4) —F, —Cl, —Br, or —I,

[0318] (5) —CO—OH,

[0319] (6) —C≡N,

[0320] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[0321] (8) —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),

[0322] (9) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one, two or three doublebonds),

[0323] (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one, two or three triplebonds),

[0324] (11) —(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl),

[0325] (12) —(CH₂)₀₋₄_C0-R_(1-aryl),

[0326] (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl),

[0327] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle),

[0328] (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from thegroup consisting of morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinylwhere each group is optionally substituted with one, two, three, or fourof: C₁-C₆ alkyl,

[0329] (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from thegroup consisting of:

[0330] (a) C₁-C₆ alkyl,

[0331] (b) —(CH₂)₀₋₂—(R_(1-aryl)),

[0332] (c) C₂-C₆ alkenyl containing one or two double bonds,

[0333] (d) C₂-C₆ alkynyl containing one or two triple bonds,

[0334] (e) C₃-C₇ cycloalkyl, and

[0335] (f) —(CH₂)₀₋₂—(R_(1-heteroaryl))

[0336] (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[0337] (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl),

[0338] (19) —(CH₂)₀₋₄—SO₂— (C₁-C₁₂ alkyl),

[0339] (20) —(CH₂)₀₋₄—SO₂— (C₃-C₇ cycloalkyl),

[0340] (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can bethe same or different,

[0341] (22) —(CH₂)₀₋₄—N(H or R_(N-5)) —CO—N(R_(N-5))₂, where R_(N-5) canbe the same or different,

[0342] (23) —(CH₂)₀₋₄-N—CS—N(R_(N-5))₂, where R_(N-5) can be the same ordifferent,

[0343] (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2) where R_(N-5) andR_(N-2) can be the same or different,

[0344] (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can bethe same or different,

[0345] (26) —(CH₂)₀₋₄—R_(N-4),

[0346] (27) —(CH₂)₀₋₄—O—CO— (C₁-C₆ alkyl),

[0347] (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂ where R_(N-aryl-1) is —Hor C₁-C₄ alkyl,

[0348] (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[0349] (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂,

[0350] (31) —(CH₂)₀₋₄-O— (R_(N-5))₂,

[0351] (32) —(CH₂)₀₋₄—O— (R_(N-5))₂—COOH,

[0352] (33) —(CH₂)₀₋₄—S—(R_(N-5))₂,

[0353] (34) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with one,two, three, four, or five —F),

[0354] (35) C₃-C₇ cycloalkyl,

[0355] (36) C₂-C₆ alkenyl with one or two double bonds optionallysubstituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0356] (37) C₂-C₆ alkynyl with one or two triple bonds optionallysubstituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-a)ryl), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0357] (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5) andR_(N-2) can be the same or different, or

[0358] (39) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl.

[0359] In yet another embodiment, R₁ and R₃ are independentlyR_(N-1)C(O)—; and R_(N-1) is R_(N-heteroaryl) where R_(N-heteroaryl) isselected from the group consisting of:

[0360] pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl,indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl,isothiazolyl, naphthyridinyl, cinnolinyl,carbazolyl, beta-carbolinyl,isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,

[0361] where the R_(N-heteroaryl) group is bonded by any atom of theparent R_(N-heteroaryl) group substituted by hydrogen such that the newbond to the R_(N-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is optionally substituted with one, two, three,or four of:

[0362] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0363] (2) —OH,

[0364] (3) —NO₂,

[0365] (4) —F, —Cl, —Br, or —I

[0366] (5) —CO—OH,

[0367] (6) —C—N,

[0368] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[0369] (8) —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),

[0370] (9) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one, two or three doublebonds),

[0371] (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one, two or three triplebonds),

[0372] (11) —(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl),

[0373] (12) —(CH₂)₀₋₄—CO—R_(1-aryl),

[0374] (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl),

[0375] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle),

[0376] (15) —(CH₂)₀₋₄—CO—R_(N-4),

[0377] (16) —(CH₂)₀₋₄—CO—O—R_(N-5),

[0378] (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[0379] (18) —(CH₂)₀₋₄—SO— (C₁-C₈ alkyl),

[0380] (19) —(CH₂)₀₋₄—SO₂— (C₁-C₁₂ alkyl),

[0381] (20) —(CH₂)₀₋₄—SO₂— (C₃-C₇ cycloalkyl),

[0382] (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can bethe same or different,

[0383] (22) —(CH₂)₀₋₄—N(H or R_(N-5)) —CO—N(R_(N-5))₂, where R_(N-5) canbe the same or different,

[0384] (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) can be the same ordifferent,

[0385] (24) —(CH₂)₀₋₄—N(—H or R_(N-5)) —CO—R_(N-2) where R_(N-5) andR_(N-2) can be the same or different,

[0386] (25) —(CH₂)₀₋₄—NRN₂RN₃ where R_(N-2) and R_(N-3) can be the sameor different,

[0387] (26) —(CH₂)₀₋₄—R_(N-4),

[0388] (27) —(CH₂)₀₋₄—O—CO— (C₁-C₆ alkyl),

[0389] (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂ where R_(N-aryl-1) is —Hor C₁-C₄ alkyl,

[0390] (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[0391] (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂,

[0392] (31) —(CH₂)₀₋₄—O— (R_(N-5))₂,

[0393] (32) —(CH₂)₀₋₄—O— (R_(N-5))₂—COOH,

[0394] (33) —(CH₂)₀₋₄—S—(R_(N-5))₂,

[0395] (34) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with one,two, three, four, or five —F),

[0396] (35) C₃-C₇ cycloalkyl,

[0397] (36) C₂-C₆ alkenyl with one or two double bonds optionallysubstituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0398] (37) C₂-C₆ alkynyl with one or two triple bonds optionallysubstituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0399] (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5) andR_(N-2) can be the same or different, or

[0400] (39) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl.

[0401] In a further embodiment, R, and R₃ are independentlyR_(N-2)C(O)—; and R_(N-1) is phenyl, 1-naphthyl, or 2-naphthyl, each ofwhich is optionally substituted with one, two or three of the followingsubstituents which can be the same or different and are:

[0402] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0403] (2) —OH,

[0404] (3) —NO₂,

[0405] (4) —F, —Cl, —Br, or —I,

[0406] (5) —CO—OH,

[0407] (6) —C—N,

[0408] (7) —(CH₂)₀₋₄-CO—NR_(N-2)R_(N-3),

[0409] (8) —(CH₂)₀₋₄—CO— (C₁-C₁₂ alkyl),

[0410] (9) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one, two or three doublebonds),

[0411] (10) —(CH₂)₀₋₄-CO— (C₂-C₁₂ alkynyl with one, two or three triplebonds),

[0412] (11) —(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl),

[0413] (12) —(CH₂)₀₋₄—CO—R_(1-aryl),

[0414] (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl),

[0415] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle),

[0416] (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from thegroup consisting of morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinylwhere each group is optionally substituted with one, two, three, or fourof: C₁-C₆ alkyl,

[0417] (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from thegroup consisting of:

[0418] (a) C₁-C₆ alkyl,

[0419] (b) —(CH₂)₀₋₂—(R_(1-aryl)),

[0420] (c) C₂-C₆ alkenyl containing one or two double bonds,

[0421] (d) C₂-C₆ alkynyl containing one or two triple bonds,

[0422] (e) C₃-C₇ cycloalkyl, and

[0423] (f) —(CH₂)₀₋₂—(R_(1-heteroaryl)),

[0424] (17) —(CH₂)₀₋₄-SO₂—NR_(N-2)R_(N-3),

[0425] (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl),

[0426] (19) —(CH₂)₀₋₄—SO₂— (C₁-C₁₂ alkyl),

[0427] (20) —(CH₂)₀₋₄—SO₂— (C₃-C₇ cycloalkyl),

[0428] (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can bethe same or different,

[0429] (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, where R_(N-5) canbe the same or different,

[0430] (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) can be the same ordifferent,

[0431] (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2) where R_(N-5) andR_(N-2) can be the same or different,

[0432] (25) —(CH₂)₀₋₄—NRN₂RN₃ where R_(N-2) and R_(N-3) can be the sameor different,

[0433] (26) —(CH₂)₀₋₄—R_(N-4),

[0434] (27) —(CH₂)₀₋₄-O—CO— (C₁-C₆ alkyl),

[0435] (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl))₂ where R_(N-aryl-1) is —H orC₁-C₄ alkyl,

[0436] (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[0437] (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂,

[0438] (31) —(CH₂)₀₋₄-O— (R_(N-5))₂,

[0439] (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH,

[0440] (33) —(CH₂)₀₋₄—S—(R_(N-5))₂,

[0441] (34) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with one,two, three, four, or five —F),

[0442] (35) C₃-C₇ Cycloalkyl,

[0443] (36) C₂-C₆ alkenyl with one or two double bonds optionallysubstituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0444] (37) C₂-C₆ alkynyl with one or two triple bonds optionallysubstituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0445] (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5) andR_(N-2) can be the same or different, or

[0446] (39) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl.

[0447] In still another embodiment, R₁ and R₃ are independentlyR_(N-1)C(O)—; and

[0448] R_(N-1) is phenyl optionally substituted with one, two or threeof the following substituents which can be the same or different andare:

[0449] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C═N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0450] (2) —OH,

[0451] (3) —NO₂,

[0452] (4) —F, —Cl, —Br, or —I,

[0453] (5) —CO—OH,

[0454] (6) —C≡N,

[0455] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[0456] (8) —(CH₂)₀₋₄—CO— (C₁-C₁₂ alkyl),

[0457] (9) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one, two or three doublebonds),

[0458] (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one, two or three triplebonds),

[0459] (11) —(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl),

[0460] (12) —(CH₂)₀₋₄—CO—R_(1-aryl),

[0461] (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl),

[0462] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle),

[0463] (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from thegroup consisting of morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinylwhere each group is optionally substituted with one, two, three, or fourof: C₁-C₆ alkyl,

[0464] (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from thegroup consisting of:

[0465] (a) C₁-C₆ alkyl,

[0466] (b) —(CH₂)₀₋₂ (R_(1-aryl)),

[0467] (c) C₂-C₆ alkenyl containing one or two double bonds,

[0468] (d) C₂-C₆ alkynyl containing one or two triple bonds,

[0469] (e) C₃-C₇ cycloalkyl, and

[0470] (f) —(CH₂)₀₋₂—(R_(1-heteroaryl)),

[0471] (17) —(CH₂) O₄—SO₂—NR_(N-2)R_(N-3),

[0472] (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl),

[0473] (19) —(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl),

[0474] (20) —(CH₂)₀₋₄—SO₂— (C₃-C₇ cycloalkyl),

[0475] (21) —(CH₂)₀₋₄—N(H or R_(N-5)) —CO—O—R_(N-5) where R_(N-5) can bethe same or different,

[0476] (22) —(CH₂)₀₋₄—N(H or R_(N-5)) —CO—N(R_(N-5))₂, where R_(N-5) canbe the same or different,

[0477] (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) can be the same ordifferent,

[0478] (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2) where R_(N-5) andR_(N-2) can be the same or different,

[0479] (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can bethe same or different,

[0480] (26) —(CH₂)₀₋₄—R_(N-4),

[0481] (27) —(CH₂)₀₋₄—O—CO— (C₁-C₆ alkyl),

[0482] (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂ where R_(N-aryl-1) is —Hor C₁-C₄ alkyl,

[0483] (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[0484] (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5)) ₂,

[0485] (31) —(CH₂)₀₋₄—O—(R_(N-5))₂,

[0486] (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH,

[0487] (33) —(CH₂)₀₋₄—S—(R_(N-5))₂,

[0488] (34) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with one,two, three, four, or five —F),

[0489] (35) C₃-C₇ cycloalkyl,

[0490] (36) C₂-C₆ alkenyl with one or two double bonds optionallysubstituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C═N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0491] (37) C₂-C₆ alkynyl with one or two triple bonds optionallysubstituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0492] (38) —(CH₂)₀₋₄—N (—H or R_(N-5)) —SO₂-R_(N-2) where R_(N-5) andR_(N-2) can be the same or different, or

[0493] (39) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl.

[0494] In another embodiment, R₁ and R₃ are independently R_(N-2)C(O)—;and

[0495] R_(N-1) is phenyl of which is optionally substituted with one,two or three of the following substituents which can be the same ordifferent and are:

[0496] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)) ,

[0497] (2) —OH,

[0498] (3) —NO₂,

[0499] (4) —F, —Cl, —Br, or —I,

[0500] (5) —CO—OH,

[0501] (6) —C≡N,

[0502] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[0503] (8) —(CH₂)₀₋₄-CO— (C₁-C₁₂ alkyl),

[0504] (9) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one, two or three doublebonds),

[0505] (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one, two or three triplebonds),

[0506] (11) —(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl),

[0507] (12) —(CH₂)₀₋₄—CO—R_(1-aryl),

[0508] (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl),

[0509] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle),

[0510] (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from thegroup consisting of morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinylwhere each group is optionally substituted with one, two, three, or fourof: C₁-C₆ alkyl,

[0511] (16) —(CH₂)₀₋₄-CO—O—R_(N-5) where R_(N-5) is selected from thegroup consisting of:

[0512] (a) C₁-C₆ alkyl,

[0513] (b) —(CH₂)₀₋₂—(R_(1-aryl)),

[0514] (c) C₂-C₆ alkenyl containing one or two double bonds,

[0515] (d) C₂-C₆ alkynyl containing one or two triple bonds, and

[0516] (e) C₃-C₇ cycloalkyl,

[0517] (17) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can bethe same or different,

[0518] (18) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, where R_(N-5) canbe the same or different,

[0519] (19) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) can be the same ordifferent,

[0520] (20) —(CH₂)₀₋₄—N(—H or R_(N-5)) —CO—R_(N-2) where R_(N-5) andR_(N-2) can be the same or different,

[0521] (21) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can bethe same or different,

[0522] (22) —(CH₂)₀₋₄—R_(N-4),

[0523] (23) —(CH₂)₀₋₄—O—CO— (C₁-C₆ alkyl),

[0524] (24) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[0525] (25) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂,

[0526] (26) —(CH₂)₀₋₄—O—(R_(N-5))₂,

[0527] (27) —(CH₂)₀₋₄—O— (R_(N-5))₂—COOH,

[0528] (28) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with one,two, three, four, or five —F),

[0529] (29) —(CH₂)₀₋₄—N(—H or R_(N-5)) —SO₂—R_(N-2) where R_(N-5) andR_(N-2) can be the same or different, or

[0530] (30) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl.

[0531] In another embodiment, R₁ and R₃ are independently R_(N-1)C(O)—;and

[0532] R₁ represents —(CH₂)_(n1)-phenyl where n₁ is zero or one andwhere phenyl is optionally substituted with one, two, or three of thefollowing substituents which are the same or different:

[0533] (A) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0534] (B) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0535] (c) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)),

[0536] (D) —F, Cl, —Br, or —I,

[0537] (E) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[0538] (F) —NR_(N-2)R_(N-3), where R_(N-2) and R_(N-3) are independentlyselected from the group consisting of:

[0539] (1) —H,

[0540] (2) —C₁-C₆ alkyl optionally substituted with one substituentselected from the group consisting of:

[0541] (a) —OH, and

[0542] (b) —NH₂,

[0543] (3) —C₁-C₆ alkyl optionally substituted with one to three —F,—Cl, —Br, or —I,

[0544] (4) —C₃-C₇ cycloalkyl,

[0545] (5) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[0546] (6) —(C₁-C₆ alkyl) —O— (C₁-C₃ alkyl),

[0547] (7) —C₂-C₆ alkenyl with one or two double bonds,

[0548] (8) —C₂-C₆ alkynyl with one or two triple bonds,

[0549] (9) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[0550] (10) —R_(1-aryl), and

[0551] (11) —R1-heteroaryl, I

[0552] (G) —OH,

[0553] (H) —C—N,

[0554] (I) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —Br,—I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)) ,

[0555] (J) —CO—(C₁-C₄ alkyl),

[0556] (K) —SO₂—NR_(1-a)R_(1-b),

[0557] (L) —CO—NR_(1-a)R_(1-b), or

[0558] (M) —SO₂—(C₁-C₄ alkyl).

[0559] In a further embodiment, R₁ and R₃ are independentlyphenyl(C₁-C₆)alkyl groups where the phenyl is optionally substitutedwith one or two groups independently selected from

[0560] (A) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F. —Cl,—Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0561] (B) —F, Cl, —Br, or —I,

[0562] (C) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[0563] (D) —NR_(N-2)R_(N-3), where R_(N-2) and R_(N-3) are independentlyselected from the group consisting of:

[0564] (1) —H,

[0565] (2) —C₁-C₆ alkyl optionally substituted with one substituentselected from the group consisting of:

[0566] (a) —OH, and

[0567] (b) —NH₂,

[0568] (3) —C₁-C₆ alkyl optionally substituted with one to three —F,—Cl, —Br, or —I,

[0569] (4) —C₃-C₇ cycloalkyl,

[0570] (5) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[0571] (6) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),

[0572] (9) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[0573] (E) —OH,

[0574] (F) —C—N,

[0575] (G) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —Br,—I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)),

[0576] (H) —CO—(C₁-C₄ alkyl),

[0577] (I) —SO₂—NR_(1-a)R_(1-b), where R_(1-a) and R_(1-b) are asdefined above, or

[0578] (J) —CO—NR_(1-a)R_(1-b), where R_(1-a) and Rlib are as definedabove.

[0579] Representative R₁ and R₃ groups also independently includebenzyl, 4-hydroxybenzyl, 2-fluoro-4-propylbenzyl, 3-amino-4-bromobenzyl;3-chloro-5-methylphenethyl, 3,5-difluorobenzyl, 2-methylphenylpropyl,4-trifluoromethylbenzyl, 4-trifluoromethylphenethyl, 2,3-dichlorobenzyl,and 2-chloro-4-cyanobenzyl.

[0580] The invention encompasses compounds of formula I, which includesthose compounds shown below wherein R₁, R₂ and R₃ are as defined above:

[0581] The invention encompasses compounds of formula I, which furtherincludes compounds shown below, wherein R₁₁ is —(CH₂)_(n1)—(R_(1-aryl)),or —(CH₂)_(n1)—O— (R_(1-aryl)), wherein nl and Riaryl are as definedabove:

[0582] The invention encompasses compounds contemplated by Formula I,and more particularly those compounds shown below:

[0583] 3-Alkyloxy-4-Furano-Piperidines

[0584] 3-Alkyloxy-4-lsoxazolo-Piperidines

[0585] The invention encompasses compounds contemplated by Formula I,and more particularly those compounds shown below:

[0586] 3,5-Alkyloxy-Piperidines

[0587] 3-Alkyloxy- and 3-Alkyl-4-Furano-Piperazines

[0588] 3-Alkyloxy- and 3-Alkyl-4Isoxazolo-Piperazines

[0589] 3-Alkyloxy- and 3-Alkyl-4-Oxazolo-Piperazines

[0590] The invention encompasses compounds contemplated by Formula I,and more specifically those compounds shown below:

[0591] The invention encompasses compounds contemplated by Formula I,and more specifically those compounds shown below:

[0592] The invention encompasses compounds contemplated by Formula I,and more specifically those compounds shown below:

[0593] The invention encompasses compounds contemplated by Formula I,and more specifically those compounds shown below:

[0594] The invention encompasses compounds contemplated by Formula II,and more specifically those compounds represented by: (II)

R₁ = R₂ = R₃ =

H,

R₆ = H, OH, NH₂

R₄ = H, OH, NH₂, NHCH₃

R₅ = H, OCH₃, CH₂CH₂OH

other alkyl, or ethyl ethers

[0595] The invention encompasses compounds contemplated by Formula I,and more specifically those compounds shown below:

[0596] The invention encompasses compounds contemplated by Formula I,and more specifically those preferred compounds shown below, where R ineach compound may independently be R₁ or R₃, and wherein R₁, R₂, R₃ Zare as defined above.

[0597] The invention encompasses compounds contemplated by Formula I,and more specifically those preferred R₂ groups as shown below. Inanother more preferred embodiement, R₂ is not a halogenated phenyl,benzyl, aryl or heteroaryl.

[0598] In yet another embodiment, the invention encompasses compoundscontemplated by Formula I, and more specifically those preferredcompounds as shown below. Possible substitutions off of the imidazolering include aryl and alkyl groups.

[0599] In yet another embodiment, the invention encompasses compoundscontemplated by Formula I, and more specifically those preferredcompounds as shown below.

[0600] In another aspect, the invention provides compounds of theformula:

[0601] or a pharmaceutically acceptable salt or ester thereof,

[0602] wherein Z′ is CH or N;

[0603] wherein R₃₀ is absent, —OH, or halo;

[0604] wherein R₄₀ is C₁₋₈ alkyl, C₁₋₈ alkoxy, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocycl, substituted heterocycl,phenyl, substituted phenyl, C₁₋₈ alkyl-phenyl, or C₁₋₈ alkyl-substittuedphenyl.

[0605] More preferably, R₃₀ is absent, —OH, or Cl, Br, I or F; furtherR₄₀ is selected from the group consisting essentially of —CH₃,—CH₂CH₂-Ph-O—CH₃, -Ph-Ph-CO₂H, -Ph-Ph-OCH₃, -Ph-Ph-C(CH₃)₃, -Ph-Ph-OCF₃,-Ph-Ph-F, -Ph-C(═O)-Ph, -Ph-Ph-CN, -Ph-Ph-NH₂, -Ph-C(CH₃)₃, —CH(CH₂CH₃)(CH₂CH₂CH₂CH₃), —CH₂CH₂Ph, -Ph-O—Ph, naphthalene, -Ph-Ph-Cl,-Ph-(OCH₃)₂, —CH₂-Ph-OCH₃, —CH₂-Ph, -Ph-Ph-S(═O)₂CH₃, -Ph-Ph, pyridyl,Ph, Ph-I, -Ph-Ph-S—CH₃, -Ph-pyridyl, -Ph-NH₂, -Ph-NO₂, -Ph-CF₃, -Ph-CH₃,-Ph-Ph-CF₃, -Ph-Ph-(OCH₃)₂, -Ph-OCH₃, -Ph-CN, —CH₂—O-Ph, -Ph-OCF₃,—CH₂-PhF₂,

[0606] In a more preferred embodiement Z is CH. In accordance with thisembodiment, a single substituent attached to a Ph-ring is in the orthoposition; alternatively, a single substituent attached to a Ph-ring isin the meta position; also alternatively, a single substituent attachedto a Ph-ring is in the para position. Further, di-substituents attachedto a Ph-ring are in di-meta positions; alternatively, di-substituentsattached to a Ph-ring are in a meta and para position.

[0607] In another aspect, the invention includes compounds of theformula

[0608] wherein R₅₀ is aryl or substituted aryl. More preferably, R₅₀ isselected form the group consisting of -Ph, -PhBr, -Ph-C(CH₃)₃, -PhF,-PhCl, -PhCN, napthyl, -Ph(CH₃)₂, -Ph-Ph, —Ph-I, -Ph-OCH₃, -PhCl₂,-Ph-PhCN, and -Ph-(OCH₃)₂. In accordance with this embodiment, a singlesubstituent attached to a Ph-ring is in the ortho position;alternatively, a single substituent attached to a Ph-ring is in the metaposition; also alternatively, a single substituent attached to a Ph-ringis in the para position. Further, di-substituents attached to a Ph-ringare in di-meta positions; alternatively, di-substituents attached to aPh-ring are in a meta and para position.

[0609] In yet another embodiment, the invention includes compounds ofthe formula

[0610] wherein R₆₀ is aryl, substituted aryl, C₁₋₆ alkyl, C₁₋₆ alkenyl,C₁₋₆ cycloalkyl, C₁₋₆ alkyl-C₁₋₆ cycloalkyl; and wherein R₇₀ ist-butoxycarbonyl or H. More preferably, R₆₀ is selected from the groupconsisting of -Ph, -Ph-Ph, napthyl, -Ph-O-Ph, -PhC(CH₃)₃, anthracinyl,-PhCH₃, -Ph(OCH₃)₂, -PhBr, -PhS(═O)₂CH₃, C(═CH₂)CH₃, cyclohexyl,—CH₂-cyclohexyl, —CH(CH₃)₂, and —CH(CH₂CH₃)₂. In accordance with thisembodiment, a single substituent attached to a Ph-ring is in the orthoposition; alternatively, a single substituent attached to a Ph-ring isin the meta position; also alternatively, a single substituent attachedto a Ph-ring is in the para position. Further, di-substituents attachedto a Ph-ring are in di-meta positions; alternatively, di-substituentsattached to a Ph-ring are in a meta and para position.

[0611] The compounds of the present invention, and pharmaceuticallyacceptable salts or esters thereof, are useful for treating humans whohave Alzheimer's disease, for helping prevent or delay the onset ofAlzheimer's disease, for treating patients with mild cognitiveimpairment (MCI) and preventing or delaying the onset of Alzheimer'sdisease in those who would progress from MCI to AD, for treating Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, diffuse Lewy body type of Alzheimer's disease. It ispreferred that the disease is Alzheimer's disease.

[0612] The compounds of the present invention are also useful to inhibitbeta-secretase and reduce or inhibit the formation of placque.

[0613] When treating these diseases, compounds of the present inventioncan either be used individually or together as is best for the patient.

[0614] With regard to these diseases the term “treating” means thatcompounds of the present invention can be used in humans with existingdisease. The compounds of the present invention will not necessarilycure the patient who has the disease but will delay or slow theprogression of the disease thereby giving the individual a more usefullife span.

[0615] The term “preventing” means that that if the compounds of thepresent invention are administered to those who do not now have thedisease but who would normally get the disease or be at increased riskfor the disease, they will not get the disease. In addition,“preventing” also includes delaying the development of the disease in anindividual who will ultimately get the disease or would be at risk forthe disease. By delaying the onset of the disease, compounds of thepresent invention have prevented the individual from getting the diseaseduring the period in which the individual would normally have gotten thedisease or reduce the rate of development of the disease or some of itseffects but for the administration of compounds of the present inventionup to the time the individual ultimately gets the disease.

[0616] In treating or preventing the above diseases the compounds of thepresent invention are administered in a therapeutically effectiveamount. The therapeutically effective amount will vary depending on theparticular compound used and the route of administration as is known tothose skilled in the art.

[0617] In treating a patient with any of the diagnosed above conditionsa physician should begin administration of one or more of the compoundsof the present invention immediately and continue indefinitely.

[0618] In treating patients who do not at the present have Alzheimer'sdisease, but who are believed to be at substantial risk for gettingAlzheimer's disease in the future, the physician should start treatmentwhen the patient first experiences early pre-Alzheimer's symptoms suchas, memory or cognitive problems associated with aging. In addition,there are some patients who are at high risk because of having thegenetic marker APOE4 which is predictive for Alzheimer's disease. Inthese situations, even though the patient does not have the disease, theadministration of the compounds of the present invention should bestarted before disease symptoms appear and treatment continuedindefinitely to prevent or delay them from possibly getting the disease.

[0619] The compounds of the present invention can be administeredorally, parenterally (IV, IM, depo-IM, SQ and depo-SQ), sublingually,intranasally (inhalation), intrathecally, topically and rectally. Theinvention here is the compounds of the present invention. There isnothing new about the routes of administration nor the dosage forms.Dosage forms known to those skilled in the art are suitable for deliveryof the compounds of the present invention.

[0620] When administered orally, the compounds of the present inventioncan be administered in usual dosage forms for oral administration as iswell known to those skilled in the art. These dosage forms include theusual solid unit dosage forms of tablets and capsules as well as liquiddosage forms such as solutions, suspensions and elixirs. When the soliddosage forms are used, it is preferred that they be of the sustainedrelease type so that the compounds of the present invention need to beadministered only once or twice daily.

[0621] The oral dosage forms are administered to the patient one .thrufour times daily. It is preferred that the compounds of the presentinvention be administered either three or fewer time, more preferablyonce or twice daily. Hence, it is preferred that the compounds of thepresent invention be administered in solid dosage form and further it ispreferred that the solid dosage form be a sustained release form whichpermits once or twice daily dosing. It is preferred that whatever dosageform is used, that it be designed so as to protect the compounds of thepresent invention from the acidic environment of the stomach. Entericcoated tablets are well known to those skilled in the art. In addition,capsules filled with small spheres each coated to protect from theacidic stomach, are also well known to those skilled in the art. Whenadministered orally the therapeutically effective amount is from about0.1 mg/day to about 3,000 mg/day, preferably about 1,000 mg/day. It ismore preferred that the oral dosage is from about 1 mg/day to about 100mg/day. It is more preferred that the oral dosage is from about 5 mg/dayto about 50 mg/day. It is understood that while a patient may be startedon one dose, that dose may have to be varied over time as the patient'scondition changes.

[0622] In addition, the compounds of the present invention can beadministered parenterally. When administered parenterally they can beadministered IV, IM, depo-IM, SQ or depo-SQ. When administeredparenterally, the compounds of the present invention should deliver atherapeutically effective amount about 0.5 to about 100 mg/day,preferably from about 5 to about 50 mg daily. When a depo formulation isused for injection once a month or once every two weeks, the dose shouldbe about 0.5 mg/day to about 50 mg/day or on a monthly amount the dosefor one month should be from about 15 mg to about 1,500 mg. Because ofthe forgetfulness of the patients with Alzheimer's disease, it ispreferred that the parenteral dosage form be a depo-IM injection.

[0623] The compounds of the present invention can be given sublingually.When given sublingually, the compounds of the present invention shouldbe given one thru four times daily in the same amount as for IMadministration.

[0624] The compounds of the present invention can be given intranasally.When given by this route of administration, the appropriate dosage formsare a nasal spray or dry powder as is known to those skilled in the art.The dosage of the compounds of the present invention for intranasaladministration is the same as for IM administration.

[0625] The compounds of the present invention can be givenintrathecally. When given by this route of administration theappropriate dosage form can be a parenteral dosage form as is known tothose skilled in the art. The dosage of the compounds of the presentinvention for intrathecal administration is the same as for IMadministration.

[0626] The compounds of the present invention can be given topically.When given by this route of administration, the appropriate dosage formis a cream, ointment or patch. Because of the amount of the compounds ofthe present invention needed to administered the patch is preferred.Further, two or more patches may be needed. When administered topically,the dosage is from about 0.5 mg/day to about 200 mg/day. However, theamount that can be delivered by a patch is limited. Therefore, two ormore patches may be required. The number and size of the patch is notimportant, what is important is that a therapeutically effective amountof the compounds of the present invention be delivered as is known tothose skilled in the art. The compounds of the present invention can beadministered rectally by suppository as is known to those skilled in theart. When administered by suppository, the therapeutically effectiveamount is from about 0.5 mg to about 500 mg.

[0627] The compounds of the present invention can be administered byimplants as is known to those skilled in the art. When administering acompound of the present invention by implant, the therapeuticallyeffective amount is the same as for depot administration.

[0628] Again, the invention here is the compounds of the presentinvention of the present invention. There is nothing novel about theroute of administration nor the dosage forms for administering thecompounds of the present invention. Given a particular compounds of thepresent invention, and a desired dosage form, one skilled in the artwould know how to prepare the appropriate dosage form for the compoundsof the present invention.

[0629] The compounds of the present invention are used in the samemanner by the same routes of administration using the samepharmaceutical dosage forms and at the same dosing schedule for treatingpatients with MCI (mild cognitive impairment) and preventing or delayingthe onset of Alzheimer's disease in those who would progress from MCI toAD, for treating Down's syndrome, for treating humans who haveHereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, fortreating cerebral amyloid angiopathy and preventing its potentialconsequences, i.e. single and recurrent lobar hemorrhages, for treatingother degenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, diffuse Lewy body type ofAlzheimer's disease.

[0630] The compounds of the present invention can be used with eachother or with other agents used to treat or prevent the conditionslisted above. Such agents include gamma-secretase inhibitors,anti-amyloid vaccines and pharmaceutical agents such as donepezilhydrochloride (ARICEPT Tablets), tacrine hydrochloride (COGNEX Capsules)or other acetylcholine esterase inhibitors and with direct or indirectneurotropic agents of the future.

[0631] In addition, the compounds of the present invention can also beused with inhibitors of P-glycoproten (P-gp). The use of P-gp inhibitorsis known to those skilled in the art. See for example, Cancer Research,53, 4595-4602 (1993), Clin. Cancer Res., 2, 7-12 (1996), CancerResearch, 56, 4171-4179 (1996), International Publications WO99/64001and WO01/10387. The important thing is that the blood level of the P-gpinhibitor be such that it exerts its effect in inhibiting P-gp fromdecreasing brain blood levels of the compounds of the present invention.To that end the P-gp inhibitor and the compounds of the presentinvention can be administered at the same time, by the same or differentroute of administration, or at different times. The important thing isnot the time of administration but having an effective blood level ofthe P-gp inhibitor.

[0632] Suitable P-gp inhibitors include cyclosporin A, verapamil,tamoxifen, quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate,progesterone, rapamycin, 10,11-methanodibenzosuberane, phenothiazines,acridine derivatives such as GF120918, FK506, VX-710, LY335979, PSC-833,GF-102,918 and other steroids. It is to be understood that additionalagents will be found that do the same function and are also consideredto be useful.

[0633] The P-gp inhibitors can be administered orally, parenterally,(IV, IM, IM-depo, SQ, SQ-depo), topically, sublingually, rectally,intranasally, intrathecally and by implant.

[0634] The therapeutically effective amount of the P-gp inhibitors isfrom about 0.1 to about 300 mg/kg/day, preferably about 0.1 to about 150mg/kg daily. It is understood that while a patient may be started on onedose, that dose may have to be varied over time as the patient'scondition changes.

[0635] When administered orally, the P-gp inhibitors can be administeredin usual dosage forms for oral administration as is known to thoseskilled in the art. These dosage forms include the usual solid unitdosage forms of tablets and capsules as well as liquid dosage forms suchas solutions, suspensions and elixirs. When the solid dosage forms areused, it is preferred that they be of the sustained release type so thatthe P-gp inhibitors need to be administered only once or twice daily.The oral dosage forms are administered to the patient one thru fourtimes daily. It is preferred that the P-gp inhibitors be administeredeither three or fewer times a day, more preferably once or twice daily.Hence, it is preferred that the P-gp inhibitors be administered in soliddosage form and further it is preferred that the solid dosage form be asustained release form which permits once or twice daily dosing. It ispreferred that what ever dosage form is used, that it be designed so asto protect the P-gp inhibitors from the acidic environment of thestomach. Enteric coated tablets are well known to those skilled in theart. In addition, capsules filled with small spheres each coated toprotect From the acidic stomach, are also well known to those skilled inthe art.

[0636] In addition, the P-gp inhibitors can be administeredparenterally. When administered parenterally they can be administeredIV, IM, depo-IM, SQ or depo-SQ. The P-gp inhibitors can be givensublingually. When given sublingually, the P-gp inhibitors should begiven one thru four times daily in the same amount as for IMadministration.

[0637] The P-gp inhibitors can be given intranasally. When given by thisroute of administration, the appropriate dosage forms are a nasal sprayor dry powder as is known to those skilled in the art. The dosage of theP-gp inhibitors for intranasal administration is the same as for IMadministration.

[0638] The P-gp inhibitors can be given intrathecally. When given bythis route of administration the appropriate dosage form can be aparenteral dosage form as is known to those skilled in the art.

[0639] The P-gp inhibitors can be given topically. When given by thisroute ofadministration, the appropriate dosage form is a cream, ointmentor patch. Because of the amount of the P-gp inhibitors needed to beadministered the patch is preferred. However, the amount that can bedelivered by a patch is limited. Therefore, two or more patches may berequired. The number and size of the patch is not important, what isimportant is that a therapeutically effective amount of the P-gpinhibitors be delivered as is known to those skilled in the art.

[0640] The P-gp inhibitors can be administered rectally by suppositoryas is known to those skilled in the art.

[0641] The P-gp inhibitors can be administered by implants as is knownto those skilled in the art.

[0642] There is nothing novel about the route of administration nor thedosage forms for administering the P-gp inhibitors. Given a particularP-gp inhibitor, and a desired dosage form, one skilled in the art wouldknow how to prepare the appropriate dosage form for the P-gp inhibitor.

[0643] It should be apparent to one skilled in the art that the exactdosage and frequency of administration will depend on the particularcompounds of the present invention administered, the particularcondition being treated, the severity of the condition being treated,the age, weight, general physical condition of the particular patient,other medication the individual may be taking as is well known to thoseskilled in the art.

[0644] The compounds of the present invention are also useful to inhibitbeta-secretase and reduce or inhibit the formation of plaque.

[0645] Inhibition of APP Cleavage

[0646] The compounds of the invention inhibit cleavage of APP betweenMet595 andAsp596 numbered for the APP695 isoform, or a mutant thereof,or at a corresponding site of a different isoform, such as APP751 orAPP770, or a mutant thereof (sometimes referred to as the “betasecretase site”. While not wishing to be bound by a particular theory,inhibition of beta-secretase activity is thought to inhibit productionof beta amyloid peptide (A-beta or Abeta). Inhibitory activity isdemonstrated in one of a variety of inhibition assays, whereby cleavageof an APP substrate in the presence of A-beta-secretase enzyme isanalyzed in the presence of the inhibitory compound, under conditionsnormally sufficient to result in cleavage at the beta-secretase cleavagesite. Reduction of APP cleavage at the beta-secretase cleavage sitecompared with an untreated or inactive control is correlated withinhibitory activity. Assay systems that can be used to demonstrateefficacy of the compound inhibitors of the invention are known.Representative assay systems are described, for example, in U.S. Pat.No. 5,942,400, 5,744,346, as well as in the examples below.

[0647] The enzymatic activity of beta-secretase and the production ofAbeta can be analyzed in vitro or in vivo, using natural, mutated,and/or synthetic APP substrates, natural, mutated, and/or syntheticenzyme, and the test compound. The analysis may involve primary orsecondary cells expressing native, mutant, and/or synthetic APP andenzyme, or may utilize transgenic animal models expressing the substrateand enzyme. Detection of enzymatic activity can be by analysis of one ormore of the cleavage products, for example, by immunoassay, flurometricor chromogenic assay, HPLC, or other means of detection. Inhibitorycompounds are determined as those having the ability to decrease theamount of beta-secretase cleavage product produced in comparison to acontrol, where beta-secretase mediated cleavage in the reaction systemis observed and measured in the absence of inhibitory compounds.Beta-secretase Various forms of beta-secretase enzyme are known, and areavailable and useful for assay of enzyme activity and inhibition ofenzyme activity. These include native, recombinant, and synthetic formsof the enzyme. Human beta-secretase is known as Beta Site APP CleavingEnzyme (BACE), Asp2, and memapsin 2, and has been characterized, forexample, in U.S. Pat. No. 5,744,346 and published PCT patentapplications WO98/22597, WO00/03819, WO01/23533, and WO00/17369, as wellas in literature publications (Mol.Cell.Neurosci. 14:419-427 (1999);Science 286:735-741 (1999); Nature 402:533-537 (1999); Nature 40:537-540(1999); and PNAS USA 97:1456-1460 (2000)). Synthetic forms of the enzymehave also been described (WO98/22597 and WO00/17369). Beta-secretase canbe extracted and purified from human brain tissue and can be produced incells, for example mammalian cells expressing recombinant enzyme.

[0648] Preferred compounds are effective to inhibit 50% ofbeta-secretase enzymatic activity at a concentration of less than about50 micromolar, preferably at a concentration of less than about 10micromolar, more preferably less than about 1 micromolar, and mostpreferably less than about 10 nanomolar.

[0649] APP Substrate

[0650] Assays that demonstrate inhibition of beta-secretase-mediatedcleavage of APP can utilize any of the known forms of APP, including the695 amino acid “normal” isotype described in Nature 325:733-6 (1987),the 770 amino acid isotype described Nature 331:530-532 (1981), andvariants such as the Swedish Mutation (KM670-1NL) (APP-SW), the LondonMutation (V7176F), and others. See, for example U.S. Pat. No. 5,766,846and also Nature Genet. 1:233-234 (1992), for a review of known variantmutations. Additional useful substrates include the dibasic amino acidmodification, APP-KK disclosed, for example, in WO 00/17369, fragmentsof APP, and synthetic peptides containing the beta-secretase cleavagesite, wild type (WT) or mutated form, e.g., SW, as described, forexample, in U.S. Pat. No. 5,942,400 and WO00/03819.

[0651] The APP substrate contains the beta-secretase cleavage site ofAPP (KM-DA or NL-DA) for example, a complete APP peptide or variant, anAPP fragment, a recombinant or synthetic APP, or a fusion peptide.Preferably, the fusion peptide includes the beta-secretase cleavage sitefused to a peptide having a moiety useful forenzymatic assay, forexample, having isolation and/or detection properties. A useful moietymay be an antigenic epitope for antibody binding, a label or otherdetection moiety, a binding substrate, and the like.

[0652] Antibodies

[0653] Products characteristic of APP cleavage can be measured byimmunoassay using various antibodies, as described, for example, inNeuro. Lett. 249:21-4 (1999) and in U.S. Pat. No. 5,612,486. Usefulantibodies to detect Abeta include, for example, the monoclonal antibody6E10 (Senetek, St. Louis, Mo.) that specifically recognizes an epitopeon amino acids 1-16 of the Abeta peptide; antibodies 162 and 164 (NewYork State Institute for Basic Research, Staten Island, N.Y.) that arespecific for human A-beta 1-40 and 1-42, respectively; and antibodiesthat recognize the junction region of beta-amyloid peptide, the sitebetween residues 16 and 17, as described in U.S. Pat. No. 5,593,846.Antibodies raised against a synthetic peptide of residues 591 to 596 ofAPP and SW192 antibody raised against 590-596 of the Swedish mutationare also useful in immunoassay of APP and its cleavage products, asdescribed in U.S. Pat. Nos. 5,604,102 and 5,721,130.

[0654] Assay Systems

[0655] Assays for determining APP cleavage at the beta-secretasecleavage site are well known in the art. Exemplary assays, aredescribed, for example, in U.S. Pat. No. 5,744,346 and 5,942,400, anddescribed in the EXAMPLES below.

[0656] Cell Free Assays

[0657] Exemplary assays that can be used to demonstrate the inhibitoryactivity of the compounds of the invention are described, for example,in WO00/17369, WO 00/03819, and U.S. Pat. Nos. 5,942,400 and 5,744,346.Such assays can be performed in cell-free incubations or in cellularincubations using cells expressing A-beta-secretase and an APP substratehaving A-beta-secretase cleavage site.

[0658] An APP substrate containing the beat-secretase cleavage site ofAPP, for example, a complete APP or variant, an APP fragment, or arecombinant or synthetic APP substrate containing the amino acidsequence: KM-DA or NL-DA, is incubated in the presence of beta-secretaseenzyme, a fragment thereof, or a synthetic or recombinant polypeptidevariant having beta-secretase activity and effective to cleave thebeta-secretase cleavage site of APP, under incubation conditionssuitable for the cleavage activity of the enzyme. Suitable substratesoptionally include derivatives that may be fusion proteins or peptidesthat contain the substrate peptide and a modification useful tofacilitate the purification or detection of the peptide or itsbeta-secretase cleavage products. Useful modifications include theinsertion of a known antigenic epitope for antibody binding; the linkingof a label or detectable moiety, the linking of a binding substrate, andthe like.

[0659] Suitable incubation conditions for a cell-free in vitro assayinclude, for example: approximately 200 nanomolar to 10 micromolarsubstrate, approximately 10 to 200 picomolar enzyme, and approximately0.1 nanomolar to 10 micromolar inhibitor compound, in aqueous solution,at an approximate pH of 4-7, at approximately 37° C., for a time periodof approximately 10 minutes to 3 hours. These incubation conditions areexemplary only, and can be varied as required for the particular assaycomponents and/or desired measurement system. Optimization of theincubation conditions for the particular assay components should accountfor the specific beta-secretase enzyme used and its pH optimum, anyadditional enzymes and/or markers that might be used in the assay, andthe like. Such optimization is routine and will not require undueexperimentation.

[0660] One useful assay utilizes a fusion peptide having maltose bindingprotein (MBP) fused to the C-terminal 125 amino acids of APP-SW. The MBPportion is captured on an assay substrate by anti-MBP capture antibody.Incubation of the captured fusion protein in the presence ofbeta-secretase results in cleavage of the substrate at thebeta-secretase cleavage site. Analysis of the cleavage activity can be,for example, by immunoassay of cleavage products. One such immunoassaydetects a unique epitope exposed at the carboxy terminus of the cleavedfusion protein, for example, using the antibody SW192. This assay isdescribed, for example, in U.S. Pat. No. 5,942,400.

[0661] Cellular Assay

[0662] Numerous cell-based assays can be used to analyze beta-secretaseactivity and/or processing of APP to release A-beta. Contact of an APPsubstrate with A-beta-secretase enzyme within the cell and in thepresence or absence of a compound inhibitor of the invention can be usedto demonstrate beta-secretase inhibitory activity of the compound.Preferably, assay in the presence of a useful inhibitory compoundprovides at least about 30%, most preferably at least about 50%inhibition of the enzymatic activity, as compared with a non-inhibitedcontrol.

[0663] In one embodiment, cells that naturally express beta-secretaseare used. Alternatively, cells are modified to express a recombinantbeta-secretase or synthetic variant enzyme as discussed above. The APPsubstrate may be added to the culture medium and is preferably expressedin the cells. Cells that naturally express APP, variant or mutant formsof APP, or cells transformed to express an isoform of APP, mutant orvariant APP, recombinant or synthetic APP, APP fragment, or syntheticAPP peptide or fusion protein containing the beta-secretase APP cleavagesite can be used, provided that the expressed APP is permitted tocontact the enzyme and enzymatic cleavage activity can be analyzed.

[0664] Human cell lines that normally process Abeta from APP provide auseful means to assay inhibitory activities of the compounds of theinvention. Production and release of A-beta and/or other cleavageproducts into the culture medium can be measured, for example byimmunoassay, such as Western blot or enzyme-linked immunoassay (EIA)such as by ELISA.

[0665] Cells expressing an APP substrate and an active beta-secretasecan be incubated in the presence of a compound inhibitor to demonstrateinhibition of enzymatic activity as compared with a control. Activity ofbeta-secretase can be measured by analysis of one or more cleavageproducts of the APP substrate. For example, inhibition of beta-secretaseactivity against the substrate APP would be expected to decrease releaseof specific beta-secretase induced APP cleavage products such as Abeta.

[0666] Although both neural and non-neural cells process and releaseA-beta, levels of endogenous beta-secretase activity are low and oftendifficult to detect by EIA. The use of cell types known to have enhancedbeta-secretase activity, enhanced processing of APP to Abeta, and/orenhanced production of A-beta are therefore preferred. For example,transfection of cells with the Swedish Mutant form of APP (APP-SW); withAPP-KK; or with APP-SW-KK provides cells having enhanced beta-secretaseactivity and producing amounts of A-beta that can be readily measured.

[0667] In such assays, for example, the cells expressing APP andbeta-secretase are incubated in a culture medium under conditionssuitable for beta-secretase enzymatic activity at its cleavage site onthe APP substrate. On exposure of the cells to the compound inhibitor,the amount of Abeta released into the medium and/or the amount of CTF99fragments of APP in the cell lysates is reduced as compared with thecontrol. The cleavage products of APP can be analyzed, for example, byimmune reactions with specific antibodies, as discussed above.

[0668] Preferred cells for analysis of beta-secretase activity includeprimary human

[0669] neuronal cells, primary transgenic animal neuronal cells wherethe transgene is APP,

[0670] and other cells such as those of a stable 293 cell lineexpressing APP, for example, APP-SW.

[0671] In Vivo Assays: Animal Models

[0672] Various animal models can be used to analyze beta-secretaseactivity and/or processing of APP to release Abeta, as described above.For example, transgenic animals expressing APP substrate andbeta-secretase enzyme can be used to demonstrate inhibitory activity ofthe compounds of the invention. Certain transgenic animal models havebeen described, for example, in U.S. Pat. Nos. 5,877,399, 5,612,486,5,387,742, 5,720,936, 5,850,003, 5,877,015 and 5,8114,633, and Nature373:523 (1995)). Preferred are animals that exhibit characteristicsassociated with the pathophysiology of AD. Administration of thecompound inhibitors of the invention to the transgenic mice describedherein provides an alternative method for demonstrating the inhibitoryactivity of the compounds. Administration of the compounds in apharmaceutically effective carrier and via an administrative route thatreaches the target tissue in an appropriate therapeutic amount is alsopreferred.

[0673] Inhibition of beta-secretase mediated cleavage of APP at thebeta-secretase cleavage site and of Abeta release can be analyzed inthese animals by measure of cleavage fragments in the animal's bodyfluids such as cerebral fluid or tissues. Analysis of brain tissues forAbeta deposits or plaques is preferred.

[0674] On contacting an APP substrate with A-beta-secretase enzyme inthe presence of an inhibitory compound of the invention and underconditions sufficient to permit enzymatic mediated cleavage of APPand/or release of Abeta from the substrate, the compounds of theinvention are effective to reduce beta-secretase-mediated cleavage ofAPP at the beta-secretase cleavage site and/or effective to reducereleased amounts of Abeta. Where such contacting is the administrationof the inhibitory compounds of the invention to an animal model, forexample, as described above, the compounds are effective to reduce Abetadeposition in brain tissues of the animal, and to reduce the numberand/or size of beta amyloid plaques. Where such administration is to ahuman subject, the compounds are effective to inhibit or slow theprogression of disease characterized by enhanced amounts of Abeta toslow the progression of AD in the, and/or to prevent onset ordevelopment of AD in a patient at risk for the disease.

[0675] Unless defined otherwise, all scientific and technical terms usedherein have the same meaning as commonly understood by one of skill inthe art to which this invention belongs.

[0676] Definitions And Conventions

[0677] The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

[0678] Definitions

[0679] Pharmaceutically acceptable refers to those properties and/orsubstances which are acceptable to the patient from apharmacological/toxicological point of view and to the manufacturingpharmaceutical chemist from a physical/chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability.

[0680] AD refers to Alzheimer's disease.

[0681] APP, amyloid precursor protein, is defined as any APPpolypeptide, including APP variants, mutations, and isoforms, forexample, as disclosed in U.S. Pat. No. 5,766,846.

[0682] A-beta (or Abeta), amyloid beta peptide, is defined as anypeptide resulting from beta-secretase mediated cleavage of APP,including peptides of 39, 40, 41, 42, and 43 amino acids, and extendingfrom the beta-secretase cleavage site to amino acids 39, 40, 41, 42, or43.

[0683] Beta-secretase (beta-secretase, BACE1, Asp2, Memapsin 2) is anaspartyl protease that mediates cleavage of APP at the amino-terminaledge of Abeta. Human beta-secretase is described, for example, inWO0/17369.

[0684] DMSO refers to dimethyl sulfoxide.

[0685] All temperatures are in degrees Centigrade.

[0686] HPLC refers to high pressure liquid chromatography.

[0687] BOC refers to 1,1-dimethylethoxy carbonyl or t-butoxycarbonyl,—CO—O—C(CH₃)₃.

[0688] Protecting group refers to t-butoxycarbonyl, benzyloxycarbonyl,formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl,iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl,1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl,1-methylcyclohexanyloxycabonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl,2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobrornyloxycarbonyl and 1-piperidyloxycarbonyl, 9-fluoroenylmethylcarbonate, —CH—CH═CH₂ and phenyl-C(═N—)—H.

[0689] Saline refers to an aqueous saturated sodium chloride solution.

[0690] Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

[0691] Pharmaceutically acceptable refers to those properties and/orsubstances that are acceptable to the patient from apharmacological/toxicological point of view and to the manufacturingpharmaceutical chemist from a physical/chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability.

[0692] A therapeutically effective amount is defined as an amounteffective to reduce or lessen at least one symptom of the disease beingtreated or to reduce or delay onset of one or more clinical markers orsymptoms of the disease.

[0693] It should be noted that, as used in this specification and theappended claims, the singular forms “a,” “an,” and “the” include pluralreferents unless the content clearly dictates otherwise. Thus, forexample, reference to a composition containing “a compound” includes amixture of two or more compounds. It should also be noted that the term“or” is generally employed in its sense including “and/or” unless thecontent clearly dictates otherwise.

[0694] Unless defined otherwise, all scientific and technical terms usedherein have the same meaning as commonly understood by one of skill inthe art to which this invention belongs. All patents and publicationsreferred to herein are hereby incorporated by reference for allpurposes.

[0695] By “alkyl” and “C₁-C₆ alkyl” in the present invention is meantstraight or branched chain alkyl groups having 1-6 carbon atoms, suchas, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl. It is understood that in cases where an alkyl chain of asubstituent (e.g. of an alkyl, alkoxy or alkenyl group) is shorter orlonger than 6 carbons, it will be so indicated in the second “C” as, forexample, “C₁-C₁₀” indicates a maximum of 10 carbons.

[0696] By “alkoxy” and “C₁-C₆ alkoxy” in the present invention is meantstraight or branched chain alkyl groups having 1-6 carbon atoms,attached through at least one divalent oxygen atom, such as, forexample, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, and3-methylpentoxy.

[0697] By the term “halogen” in the present invention is meant fluorine,bromine, chlorine, and iodine.

[0698] “Alkenyl” and “C₂-C₆ alkenyl” means straight and branchedhydrocarbon radicals having from 2 to 6 carbon atoms and from one tothree double bonds and includes, for example, ethenyl, propenyl,1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like.

[0699] “Alkynyl” and “C₂-C₆ alkynyl” means straight and branchedhydrocarbon radicals having from 2 to 6 carbon atoms and one or twotriple bonds and includes ethynyl, propynyl, butynyl, pentyn-2-yl andthe like.

[0700] As used herein, the term “cycloalkyl” refers to saturatedcarbocyclic radicals having three to twelve carbon atoms. The cycloalkylcan be monocyclic, or a polycyclic fused system. Examples of suchradicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Preferred cycloalkyl groups are cyclopentyl, cyclohexyl, andcycloheptyl. The cycloalkyl groups herein are unsubstituted or, asspecified, substituted in one or more substitutable positions withvarious groups. For example, such cycloalkyl groups may be optionallysubstituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl.

[0701] By “aryl” is meant an aromatic carbocyclic group having a singlering (e.g., phenyl), multiple rings (e.g., biphenyl), or multiplecondensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-,or trisubstituted. Preferred aryl groups of the present invention arephenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl,tetralinyl or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. The arylgroups herein are unsubstituted or, as specified, substituted in one ormore substitutable positions with various groups. For example, such arylgroups may be optionally substituted with, for example, C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino,mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,mono(C₁-C₆)alkylamino(C₁-C₆)alkyl or di(C₁-C₆) alkylamino (CL-C₆) alkyl.

[0702] By “heteroaryl” is meant one or more aromatic ring systems of 5-,6-, or 7-membered rings which includes fused ring systems of 9-11 atomscontaining at least one and up to four heteroatoms selected fromnitrogen, oxygen, or sulfur. Preferred heteroaryl groups of the presentinvention include pyridinyl, pyrimidinyl, quinolinyl, benzothienyl,indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl,isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl,isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. The heteroarylgroups herein are unsubstituted or, as specified, substituted in one ormore substitutable positions with various groups. For example, suchheteroaryl groups may be optionally substituted with, for example, C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino,mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,mono(C₁-C₆)alkylamino(C₁-C₆)alkyl or di(C₁-C₆) alkylamino (C₁-C₆) alkyl.

[0703] By “heterocycle”, “heterocycloalkyl” or “heterocyclyl” is meantone or more carbocyclic ring systems of 4-, 5-, 6-, or 7-membered ringswhich includes fused ring systems of 9-11 atoms containing at least oneand up to four heteroatoms selected from nitrogen, oxygen, or sulfur.Preferred heterocycles of the present invention include morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide,piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl,homopiperidinyl, homomorpholinyl, homothiomorpholinyl,homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl,dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide. Theheterocycle groups herein are unsubstituted or, as specified,substituted in one or more substitutable positions with various groups.For example, such heterocycle groups may be optionally substituted with,for example, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro,amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,mono(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl or═O.

[0704] Modes of Preparation

[0705] Compounds of the invention can be prepared utilizing a variety ofknown chemical transformations. The compounds of the invention can beprepared by one skilled in the art without more just by knowing thechemical structure of the compound. The chemistry is known to thoseskilled in the art. In fact, there is more than one process to preparethe compounds of the invention. Exemplary methods of preparation can befound in the art. For example, see A Short Formal Synthesis ofParoxetine. Diastereoselective Cuprate Addition of a Chiral RacemicOlefinic Amido Ester, Coss, J., et al., Tetrahedron Letters, 42 (2001,7805-7807; Solid-Phase Synthesis of Aspartic Peptidas Inhibiors:3-Alkoxy-4-Aryl Piperidines, Bursavich, Matthew, et. al., OrganicLetters, 2001, Vol. 3, No. 17, 2625-2628; and From Peptides toNon-Peptide Peptidomimetics: Design and Synthesis of New PiperidineInhibitors of Aspartic Peptidases, Bursavich, Matthew, et. al., OrganicLetters, 2001, Vol. 3, No. 15, 2317-2320; and the references citedtherein, all incorporated in by the entirety.

[0706] In addition to the methods above, a variety of additionalsynthetic routes may be utilized to prepare the compounds of theinvention as shown in more detail below. Representative procedures forthe preparation of compounds are set forth below in the various schemes.The R-groups shown in the schemes are generally representative of R₁,R₂, R₃, and R₄ as set forth herein.

[0707] Synthetic Routes to 3,5-Disubstituted-piperidines

[0708] Any enolizable aldehyde capable of forming an enamine shouldreact to form 3, leading to a wide variety of substituents which end upat C-3. R can be alkyl chain of 1-6 carbons, straight-chained orbranched, cycloalkylmethyl, phenylmethyl, or phenyl-substituted alkylchain of 1-6 carbons, either straight-chained or branched. Bothenantiomers of 5, commercially available, which can therefore give riseto both enantiomers of 6. R¹ can be the same or different as R, definedabove, where X is a “good leaving” group such as, Br, Cl, I, Tosly,Mesyl, etc. Other electrophilic reagents such as acid chlorides,sulfonyl chlorides, chloroformates and also make up R¹—X.

[0709] There are numerous ways to introduce and oxygen a to the amidecarbonyl. Only one such method is shown. R is defined as above. R¹—Xdefined as above.

[0710] Synthetic Routes to 3,4-disubstituted and 3,4,5-trisubstitutedpiperidines

[0711] Compound 10 is known in the literature (Tet.Asymm, 1996, 7, 867).R is defined as above, with the addition of being phenyl, substitutedphenyl, heteroaromatic rings, cycloalkyl rings, or substitutedcycloalkyl rings of 3-8 members. The reaction sequence will also work ifalkyl lithium cuprates are substituted for the Grignard reagent, RMgBr.

[0712] Compound 15 is known in the literature where R-Ethyl (Org Lett,2001, 3, 611). It can be prepared readily from 6, where R is defined asabove. R¹ can be the same as or different from R and defined as above. Ris defined as above, with the addition of being phenyl, substitutedphenyl, heteroaromatic rings, cycloalkyl rings, or substitutedcycloalkyl rings of 3-8 members.

[0713] Compound 19 can be prepared analogously to 16 above. R and R1 aredefined above. R2 can be the same or different as R or R1.

[0714] Complimentary ivfethods of Piperidine Synthesis:

[0715] Dimethyldinicotinate is hydrogenated over Adam's catalyst in ACOHto give the piperidine 1. The esters are then reduced by LAH, thenprotected with Boc anhydride to give the diol 2, which is alkylatedunder Williamson-type conditions to give either mono-alkyl 3. orbis-alkyl 4. Removal of the Boc group yields the final compound.

[0716] Fischer esterification of 5-bromonicotinic acid gives the ester1, which can be coupled with an arylmetalloid under Pd catalyzedconditions to give 2.Reduction of the nicotinate ester may beaccomplished by Adam's catalyst to give 3. This can be further reducedby the action of LAH on the ester, and the resulting compoundN-protected to give 4. Alkylation gives 5, and the removal of thecarbamate gives the desired 6.

[0717] Nicotinic acid, 1, is subjected to a Fowler reduction, givingcompound 2. Further reduction gives the enoate 3. Addition of an alkylcuprate will substitute the 4 position of the piperidine to give 4 (if His desired, Rh catalyzed hydogcnation is used), the ester of which canbe reduced by LAH to give te primary alcohol, 5. The alcohol can beallylated to give 6, and the amine deprotected to give 7. (Org. Lett.,2001, 3, 210)

[0718] 5-Hydroxynicotinic acid is subjected to Fowler reduction to givethe keto-enoate 2, and reduction of the carbonyls gives the diol 3,alkylation of the primary alcohol to give 4 s followed by furtheralkylation to give 5. Peprotection of the amine gives compound 6. (Org.Lett 2001, 3, 210)

[0719] Additional alternatives methods of synthesis of the compounds arecontemplated by the invention as shown in more detail below, for thesubject compounds indicated.

[0720] Exemplifications of the Invention may be made as taught by Lesmaet al., J. Org. Chem., 1998, 63, 3492(and references cited therein):

[0721] Exemplifications of the Invention may be made as taught by Yu etal. Tetahedron Lett., 2000, 41, 547 (and references cited therein):

[0722] Exemplifications of the Invention may be made as taught byGmeinert et al J. Org. Chem., 2081, 66,7408 (and references citedtherein):

[0723] Exemplifications of the Invention may be made as taught by et al.J. Org. Chem., 2000, 86, 7432 (and references cited therein):

[0724] Exemplifications of the Invention may be made as taught by Liraset al Org. Lett., 2001, 3, 3483 (and references cited therein).

[0725] Exemplifications of the Invention may be made as taught byLiebeskind et al. Org. Lett., 2001,3, 3381 (and references citedtherein):

[0726] Exemplifications of the Invention may be made as taught by Beaket e J. Am. Chem. Soc 2001, 123.1004 (and references cited therein):

[0727] Exemplifications of the Invention may be made as taught by Hayshiet al. J. Org. Chem., 2001, 668 6852 (and references cited therein)

[0728] Exemplifications of the Invention may be made as taught by Ganemet al. Org Lett. 2001, 3, 201 (and references cited therein):

[0729] Exemplifications of the Invention may be made as taught by Liu etal. Tetrahedron: Asymmetry, 2001, 12, 419 (and references citedtherein):

[0730] Exemplifications of the Invention may be made as taught by Sabolet al. Tetrahedron Lett., 2001, 42, 1631 (and references cited therein):

[0731] Exemplifications of the Invention may be made as taught by Diazet al. Tetrahedron Lett. 2001, 42, 871 (and refcrences cited therein):

[0732] Exemplifications of the Invention may be made as taught byBuchner & Metz Tetrahedron Lett., 2001. 4Z 5381 (and references citedtherein):

[0733] Exemplifications of the Invention may be made a taught by Cossyet al. Tetrahedron Lett., 2001, 42, 5705 (and references cited therein):

[0734] Exemplifications of the Invention may be made s taught byZacharia ei a. J. Org. Chem. 2001, 60,5264 (and references citedtherein):

[0735] Exemplifications of the Invention may be tnda as bught by Pandey& Kapur Synthesis 2001, 1263 (and references cited therein):

[0736] Exemplifications of the Invention may be made as taught by Ametet al. Org. Lett. 2001, 3, 611 (and references cited therein):

[0737] Exemplifications of the Invention may be made as taught by Amatet al. Org. Lett. 2001, 3, 3257 (and references cited therein):

[0738] In accordance with the above preparative schemes, Example 1 wasprepared as described below.

EXAMPLE 1

[0739] (+/−)-(3R,4R)-4-(3-hydroxyphenyl)piperidin-3-yl1,1′-biphenyl-4-carboxylate hydrochloride

[0740] Step 1: Preparation of tert-Butyl4-(3-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0741] The tert-butyl4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate(6.42 g, 9.23 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 4.69 g, 21.3 mmol,and tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol) weremixed in dioxane (20 mL), ethanol (10 mL) and 2 M aqueous sodiumcarbonate (5.0 mL). The solution was refluxed for 4 hours, cooled toroom temperature, and poured into ethyl acetate (150 mL). The solutionwas extracted with 1N aqueous hydrochloric acid (2×100 mL), filteredthrough celite, extracted with saturated aqueous sodium bicarbonate(2×100 mL), and extracted with saturated with saturated aqueous ammoniumchloride (2×100 mL). The solution was dried over sodium sulfate, vacuumfiltered through a bed of silica gel and solvent removed at reducedpressure to afford a red oil. The tert-butyl4-(3-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (5.3 g, 19.2mmol) was obtained as a combination of two crystallization crops fromdichloromethane/hexane crystallization solvents. HRMS m/z 276.1614(calcd for M+H 276.1594)

[0742] Step 2: Preparation of tert-Butyl4-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0743] The tert-butyl4-(3-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4.01 g, 14.58mmol), tert-butyldimethylsilyl chloride (2.73 g, 18.22 mmol),triethylamine (4.01 g, 40.0 mmol) and a catalytic amount ofdimethylaminopyridine (100 mg, 0.80 mmol) were mixed in dichloromethane(100 mL) at room temperature for 16 h. The solvent was removed atreduced pressure and the resulting semisolid dissolved in diethylether(100 mL). The solution was extracted with 1N aqueous hydrochloric acid(2×50 mL), extracted with saturated aqueous sodium bicarbonate (2×50mL), and extracted with saturated with saturated aqueous ammoniumchloride (2×50 mL). The solution was dried over sodium sulfate andsolvent removed at reduced pressure. The tert-butyl4-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate(4.8 g, 12.33 mmol) was isolated as a clear colorless oil by preparativesilica chromatography (5% ethyl acetate/95% hexanes). HRMS m/z 388.2305(calcd for M−H 388.2302)

[0744] Step 3: Preparation of (+/−)-tert-Butyl(3S,4S)-4-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-hydroxypiperidine-1-carboxylate

[0745] The tert-butyl4-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3,6-dihydropyridine-l(2H)-carboxylate(4.61 g, 11.85 mmol) was dissolved in tetrhydrofuran (50 mL). Thesolution was cooled to 0° C. and borane-methyl sulfide complex (1.79 g,23.7 mmol) was slowly added. The solution was heated to reflux for 2Hand cooled to room temperature. 1 M aqueous sodium hydroxide solution(30 mL) was added dropwise to control the gas evolution. 35% Aqueoushydrogen peroxide (45 mL) was added and solution refluxed for 2H. Thesolution was cooled to room temperature and poured into diethylether(200 mL). The solution was extracted with 2.5 M aqueous sodium hydroxide(2×75 mL) and the organic layer checked for peroxides with starch iodidepaper. The organic layer extracted with saturated ammonium chloride(1×50 mL) and dried over sodium sulfate. The (+/−)-tert-butyl(3S,4S)-4-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-hydroxypiperidine-1-carboxylate(2.3 g, 5.65 mmol) as a semi solid by preparative silica chromatography(0-10% ethyl acetate/hexanes). HRMS m/z 408.2564 (calcd for M+H408.2565)

[0746] Step 4: Preparation of (+/−)-tert-Butyl(3R,4R)-3-[(1,1′-biphenyl-4-ylcarbonyl)oxy]-4-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)piperidine-1-carboxylate

[0747] The (+/−)-tert-butyl(3S,4S)-4-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-hydroxypiperidine-1-carboxylate(206 mg, 0.51 mmol), ,1′-biphenyl-4-carbonyl chloride (540 mg, 2.50mmol), triethylamine (400 mg, 4.00 mmol), and a catalytic amount ofdimethylaminopyridine (10.0 mg, 0.08 mmol) was mixed together inacetonitrile (10.0 mL) at room temperature for 16H. Ammonium hydroxidesolution (5 mL) was added to the solution and it was stirred for 1H. Theheterogeneous solution was poured into ethyl acetate (50 mL) and hexanes(5 mL). The solution was extracted with 1N aqueous hydrochloric acid(2×10 mL), extracted with saturated aqueous sodium bicarbonate (2×10mL), and extracted with saturated with saturated aqueous ammoniumchloride (2×10 mL). The solution was dried over sodium sulfate andsolvent removed at reduced pressure. The (+/−)-tert-butyl(3R,4R)-3-[(1,1′-biphenyl-4-ylcarbonyl)oxy]-4-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)piperidine-1-carboxylate(164 mg, 0.28 mmol) was isolated as a semisolid by radial silica gelchromatography (25% ethyl acetate/hexanes). HRMS m/z 588.3150 (calcd forM+H 588.3140)

[0748] Step 5: Preparation of(+/−)-(3R,4R)-4-(3-Hydroxyphenyl)piperidin-3-yl1,1′-biphenyl-4-carboxylate hydrochloride

[0749] The (+/−)-tert-butyl(3R,4R)-3-[(1,1′-biphenyl-4-ylcarbonyl)oxy]-4-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)piperidine-1-carboxylate(91 mg, 0.16 mmol) was dissolved in 4 N Hydrogen chloride in dioxanes(3.0 mL). The solution was stirred for 4H at room temperature anddiethylether (10 mL) was added. The solution was kept at roomtemperature for 16H and solids formed. The(+/−)-(3R,4R)-4-(3-hydroxyphenyl)piperidin-3-yl1,1′-biphenyl-4-carboxylate hydrochloride (56 mg, 0.13 mmol) wasobtained as a white solid. HRMS m/z 374.1753 (calcd for M+H 374.1751)

[0750] The invention is illustrated further by the following exampleswhich are not to be construed as limiting the invention in scope orspirit to the specific procedures described in them.

[0751] Examples 2 through 60, as represented by the structures shownbelow, were prepared using similar procedures as those described above.Example land examples 2-60 are shown below: Exact Mass Calc. ExactStructure Compound Name(s) (m + H) Mass (M + H) Example 1

(+/−)-(3R,4R)-4-(3- hydroxyphenyl)piperidin-3-yl 1,1′-biphenyl-4-carboxylate hydrochloride 374.1753 374.1784 Example 2

(+/−)-(3R,4R)-4-(4- chlorophenyl)piperidin-3-yl 1,1′-biphenyl-4-carboxylate trifluoroacetate 392.1417 392.1418 Example 3

(+/−)-(3R,4R)-4-(4- chlorophenyl)piperidin-3-yl(3,5-difluorophenyl)acetate 366.1072 366.1072 Example 4

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 1-naphthoate hydrochloride358.1785 358.1802 Example 5

(+/−)-(3R,4R)-4-(4- fluorophenyl)piperidin-3-yl 1,1-biphenyl-4-carboxylate trifluoroacetate 376.1713 3761303 Example 6

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 4-(trifluoromethoxy)benzoatehydrochloride 366.1292 366.1317 Example 7

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 4-iodobenzoate hydrochloride408.0429 408.0461 Example 9

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl phenoxyacetate hydrochloride312.1598 312.16 Example 10

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 4-(trifluoromethyl)benzoatehydrochloride 350.1381 350.1368 Example 11

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 4-cyanobenzoate hydrochloride307.1413 307.1441 Example 12

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 3-methylbenzoate trifluoroacetate296.1644 296.1645 Example 13

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 3-methoxybenzoate trifluoroacetate312.1623 312.1595 Example 14

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 2-methoxybenzoate hydrochloride312.1610 312.1594 Example 15

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl benzoate hydrochloride 282.1470282.1489 Example 16

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 3′,4′-dimethoxy-1,1′-biphenyl-4-carboxylate hydrochloride 418.2020 418.2013 Example 17

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 4-(5-chlorothien-2- yl)benzoatehydrochloride 398.0959 398.0976 Example 18

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 4′-(trifluoromethyl)-1,1′-biphenyl-4-carboxylate hydrochloride 426.1671 426.1675 Example 19

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 2-methylbenzoate hydrochloride296.1622 296.1645 Example 20

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 3-(trifluoromethyl)benzoatehydrochloride 350.1351 350.1362 Example 21

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 4-nitrobenzoate hydrochloride327.1330 327.1339 Example 22

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 2-naphthoate hydrochloride332.1631 332.1645 Example 23

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 4-aminobenzoate dihydrochloride297.1615 297.1598 Example 24

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 4-pyridin-4-ylbenzoatedihydrochloride 359.1733 359.1754 Example 25

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 4′-(methylthio)-1,1′-biphenyl-4-carboxylate hydrochloride 404.1684 404.0455 Example 26

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 3-iodobenzoate hydrochloride408.0455 407.0382 Example 27

(+/−)-(3R,4R)-4-(3- hydroxyphenyl)piperidin-3-yl benzoate hydrochloride298.1463 298.1438 Example 28

(+/−)-(3R,4R)-4-(3- hydroxyphenyl)piperidin-3-yl benzoate hydrochloride283.1428 283.1441 Example 29

(3R,4R)-4- phenylpiperidin-3-yl 1,1′-biphenyl-4-carboxylate 326.1760326.1751 Example 30

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 1,1′-biphenyl-3- carboxylatehydrochloride 358.1835 358.1802 Example 31

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 4-thien-2-ylbenzoate hydrochloride364.1387 364.1366 Example 32

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 4′-(methylsulfonyl)-1,1′-biphenyl-4-carboxylate hydrochloride 436.1559 436.1577 Example 33

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl phenylacetate hydrochloride296.1621 296.1645 Example 34

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl (3-methoxyphenyl)acetatetrifluoroacetate 326.1733 326.1751 Example 35

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 3,4-dimethoxybenzoatetrifluoroacetate 342.1697 342.1700 Example 36

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl (1R,2S)-2-phenylcyclopropanecarboxylate hydrochloride 322.1806 322.1802 Example 37

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 3′-chloro-1,1′-biphenyl-4-carboxylate hydrochloride 392.1420 392.1412 Example 38

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 4′-chloro-1,1′-biphenyl-4-carboxylate hydrochloride 392.1420 392.1412 Example 39

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 1-naphthoate hydrochloride332.1671 332.1645 Example 40

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 4-phenoxybenzoate hydrochloride374.1751 374.1751 Example 41

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 3-phenylpropanoatetrifluoroacetate 310.1795 310.1802 Example 42

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 2-ethylhexanoate hydrochloride304.2234 304.2271 Example 43

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 4-tert-butylbenzoate hydrochloride338.2143 338.2120 Example 44

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 3′-amino-1,1′-biphenyl-4-carboxylate dihydrochloride 373.1887 373.1916 Example 45

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 3-(5-chlorothien-2-yl) benzoatehydrochloride 398.1016 398.0981 Example 46

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 3′-cyano-1,1′-biphenyl-4-carboxylate hydrochloride (Generated by ACD/Name software) 373.1767383.1754 Example 47

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 2,2′-bithiophene-5- carboxylatehydrochloride 370.0908 370.0935 Example 48

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 5-phenylthiophene-2- carboxylatehydrochloride 364.1335 364.1371 Example 49

(+/−)-(3S,4R)-4-[(1R)- cyclohexa-2,4-dien-1- yl]piperidin-3-yl4-benzoylbenzoate hydrochloride) 386.1778 386.1756 Example 50

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 4′-fluoro-1,1′-biphenyl-4-carboxylate hydrochloride 376.1679 376.1707 Example 51

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl4′-(trifluoromethoxy)-1,1′-biphenyl-4- carboxylate hydrochloride442.1607 442.1625 Example 52

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 5-pyridin-2-ylthiophene-2-carboxylate dihydrochloride 365.1336 365.1318 Example 53

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]benzoate hydrochloride 416.1566 416.158 Example 54

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 4′-tert-butyl-1,1′-biphenyl-4-carboxylate hydrochloride 414.2417 414.2428 Example 55

(+/−)-(3S,4S)-4- phenylpiperidin-3-yl 4′-methoxy-1,1′-biphenyl-4-carboxylate hydrochloride 388.1936 388.1907 Example 56

(+/−)-4′-({[(3S,4S)-4- phenylpiperidin-3- yl]oxy}carbonyl)-1,1′-biphenyl-4-carboxylic acid hydrochloride 402.1706 402.1700 Example 57

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl 3-(4-methoxyphenyl)propanoatehydrochloride 340.1888 340.1907 Example 59

(+/−)-(3R,4R)-4- phenylpiperidin-3-yl acetate hydrochloride 220.1332220.1334 Example 60

(+/−)-(3R,4R)-4-pyridin- 3-ylpiperidin-3-yl acetate dihydrochloride460.1815 460.1788

[0752] Examples 61-79 were prepared in accordance with the abovesynthetic routes as shown below: Ion Found Example Structure FW (ES+) 61

191.28 192.1 62

270.17 272.1 63

270.17 270.1 64

247.38 248.3 65

209.27 210.1 66

259.27 260.2 67

225.72 226.1 68

216.29 217.2 69

241.34 242.2 70

219.33 220.2 71

267.37 268.2 72

317.17 318.1 73

221.3 222.2 74

260.17 260.1 75

292.38 293.3 76

251.33 252.2 79

297.4 298.2

[0753] Examples 80 was also prepared in accordance with the abovesynthetic routes as described herein:

EXAMPLE 80

[0754]

[0755] OAMS supporting ions at: ESI+298.2

[0756] [α]²⁵ _(D)=0° (c 0.72, chloroform).

[0757] Anal. Calcd for C₁₉H₂₃NO₂: C, 76.74; H, 7.80; N, 4.71.

[0758] Found: C, 76.46; H, 7.76; N, 5.00.

[0759] In another embodiment, 3-alkoxy-5-alkyl piperidines of theinvention may be prepared utilizing the routes shown below and asdescribed:

[0760] Preparation of 3-alkyl-5-benzyloxy Piperdines

[0761] To a THF (100 ml) solution of 1 (5.4 g, 26.6 mmol) (JOC, 1986,51, 3140), at −78° C., was added LIHMDS (28 ml, 28 mmol, 1.0M in THF).The mixture was stirred for 1 hour followed by addition of benzylbromide and allowed to warm to room temperature. After stirringovernight at r.t. the reaction was quenched with sat'd aq. NH₄Cl (75 ml)and extracted with EtOAc. The organic layer was washed NaHCO₃ (50 ml),brine 50 ml), and dried over MgSO₄ to give 4.9 g of 2 (64%) as a mixtureof diastereomers. Flash chromatography 10% EtOAc/Heptane to 65%EtOAc/heptane yields 2.9 g of the trans isomer and 2.1 g of the cisisomer.

[0762] To a refluxing THF (8 ml) suspension of LiAl₄ (0.46 g, 12.3 mmol)was added a THF (8 ml) solution of 2 (2.4 g, 8.2 mmol) (Biotech & Bioeng1998/99, 61, 143). The reaction was maintained at reflux for 12 hfollowed by cooling to 0° C. and the slow addition of sat's aq. NaSO₄.The mixture was diluted with EtOAc and filtered through Celite and thefiltrate dried over MgSO₄. Concentration in vacuo gave 2.2 g of 3 (85%)as a clear oil. To a THF (60 ml) solution of 3 (2.2 g, 7.8 mmol) wasadded TFAA (2.5 g, 11.7 mmol) dropwise followed by warming to r.t. After1.5 h at r.t. Et₃N (4.3 ml, 31.2 mmol) was added dropwise followed byheating at reflux for 40 h. After cooling to r.t. the mixture wastreated with 10% NaOH and stirred for 1 h. The mixture was diluted withEtOAc (75 ml) and washed with NaHCO₃ (2×20 ml), brine (20 ml) and theorganic layer dried over Na₂SO₄. Flash chromatography 5% MeOH/CHCl₃ gave1.6 g of 4 (73%).

[0763] A parr apparatus was charged with Pd/C 0.470 mg and 4 (1.26 g,4.5 mmol) in 40 ml of MeOH. The apparatus was charged with 40 psi. H₂and shaken at r.t. for 6 h. The reaction mixture was filtered throughCelite and conc. in vacuo. The resulting residue was dissolved in THF(30 ml) followed by the addition of Boc₂O (1.2 g, 5.4 mmol). Afterstirring at r.t for 3 h the reaction was diluted with EtOAc (70 ml) andwashed with H₂O (3×20 ml). The organic layer was dried over MgSO₄ andconcentrated in vacuo to yield 5 (0.74 g, 57%) as a white solid afterflash chromatography 50% EtOAc/heptane.

EXAMPLE 82

[0764] 3-benzyl-5-[(3,5-difluorobenzyl)oxy]piperidine hydrochloride.

[0765] Compound 5 (0.10 g , 0.34 mmol) in THF (1 ml) was treated with0.7 ml of 1.0 M t-BuOK in THF and stirred for 15 min. at r.t. Themixture was treated with 2.0 eq. of 3,5-difluorobenzyl bromide andstirred at 50° C. for 18 h. The mixture was diluted with 5 ml of MeOHfollowed by the addition of 1 g of DOWEX® 50×2-400 ion-exchange resinand stirred at 45° C. for 5 h. The resin was collected by filtration andwashed with MeOH and CH₂Cl₂ (3×10 ml). The resin was then treated with7N NH₃/MeOH to elute the final compound. The desired salt was obtainedby treating the amine with either HCl or TFA in Et₂O.

[0766] HRMS m+H=318.1663

[0767] The following were prepared according to the methods describedfor example 82.

EXAMPLE 83 3-benzyl-5-[(3-methylbenzyl)oxy]piperidine hydrochloride.HRMS m+H=296.2012. EXAMPLE 843-benzyl-5-{[4-(trifluoromethyl)benzyl]oxy}piperidine hydrochloride.HRMS m+H=349.1653 EXAMPLE 853-({5-benzylpiperidin-3-yl]oxy}methyl)benzonitrile. HRMS m+H=307.1807.EXAMPLE 86 3-benzyl-5-[(3-methoxybenzyl)oxy]piperidine hydrochloride.HRMS m+H=312.1965. EXAMPLE 87 5-benzylpiperidin-3-yl1,1′-biphenyl-4-carboxylate trifluoroacetate. HRMS m+H=372.1953

[0768]

[0769]4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (2). A solution oft-butyl-4-oxopiperidine-1-carboxylate (6.50 g, 32.6 mmol) in THF (50 mL)was added dropwise to a stirred solution of LDA (24 mL, 35.8 mmol, 1.1eq., 1.5 M in hexanes) in THF (50 mL) at −78° C. After stirring for 30min, a solution of N-phenyltrifluoromethanesulfonamide (12.48 g, 35.0mmol, 1.07 eq.) in THF was added. The reaction mixture was stirred underinert atmosphere for 6 h at 0° C. The reaction was concentrated in vacuoand filtered over a pad of alumina (hexanes/EtOAc 9:1) to afford 2 as apale yellow oil which was used without further purification (10.26 g,95%).

[0770] 4-Furan-3-yl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butylester (4). A flask was charged with boronic acid 3 (6.22 g, 55.6 mmol),triflate 2 (55.27 g, 166.8 mmol, 3 eq.), lithium chloride (7.07 g, 166.8mmol, 3 eq.), aqueous 2N Na₂CO₃ (56 mL), 1,2-dimethoxyethane (120 mL)and Pd(PPh₃)₄ (3.21 g, 2.8 mmol, 0.05 eq.). The reaction mixture washeated to reflux under inert atmosphere for 4 h. After cooling to roomtemperature the reaction mixture was concentrated under reducedpressure. The resulting residue was partitioned between dichloromethane(150 mL), aqueous 2N Na₂CO₃ (125 mL), and concentrated ammoniumhydroxide (9 mL). The layers were separated and the aqueous layerextracted again with dichloromethane (3×125 mL). The combined organicswere dried over anhydrous magnesium sulfate and concentrated in vacuo.The resulting residue was purified via flash column chromatography(hexanes/CH₂Cl₂/EtOAc 9:1:1) to yield 4 as a light yellow oil (8.13 g,59%). TLC R_(f)=0.43; 400 MHz ¹H-NMR (CDCl₃) δ 1.48 (s, 9H), 2.37 (s,2H), 3.60 (t, J=3.6 Hz, 2H), 4.03 (s, 2H), 5.87 (s, 1H), 6.51 (s, 1H),7.38 (d, J=6.8 Hz, 2H); 125 MHz ¹³C-NMR (CDCl₃) δ 26.9, 39.5 (broad),40.8 (broad), 43.6 (broad), 79.7, 107.2, 118.7 (broad), 126.8, 138.1,143.5, 154.9. HRMS Calcd. for C₁₄H₁₉NO₃Na [M⁺+Na] 272.1263. Found:272.1271.

[0771] 4-Furan-3-yl-3-hydroxy-piperidine-1-carboxylic acid tert-butylester (5). To a solution of 4 (2.33 g, 9.358 mmol) in THF (10 mL) at 0°C. borane-tetrahydrofuran, BH₃-THF (28.07 mL, 28.07 mmol, 3 eq., 1M sol.in THF) was added dropwise. After stirring the reaction mixture underinert atmosphere at room temperature for 3 h, the unreacted borane wasquenched by the addition of methyl alcohol (30 mL). After quenching, 3NNaOH (30 mL) was added slowly to the reaction mixture. This was followedby the addition of 30% H₂O₂ (15 mL). The reaction mixture was stirredunder inert atmosphere at room temperature for 16 h. Solvents wereremoved under reduced pressure and the crude mixture was dissolved inethyl acetate (60 mL). The ethyl acetate solution was washed with water(40 mL), bicarbonate solution (40 mL), water (40 mL), and brine (40 mL),dried over anhydrous magnesium sulfate and filtered. Removal of solventat reduced pressure yielded the pure, white, crystalline solid 5 (2.18g, 87%). TLC Rf=0.48 (95% CH₂Cl₂—MeOH); 400 MHz ¹H-NMR (CDCl₃) δ 1.47(s, 9H), 1.57-1.69 (m, 1H), 1.82-1.85 (m, 0.5H), 1.86-1.88 (m, 0.5H),2.50 (ddd, J=12.4, 10.0, 4.0 Hz, 1H), 2.62 (t, J=10.8 Hz, 1H), 2.76 (m,1H), 3.47 (m, 1H), 4.12 (m, 1H), 4.32 (m, 1H), 6.35 (s, 1H), 7.38 (d,J=18.8 Hz, 2H); 125 MHz ¹³C-NMR (CDCl₃) δ 14.4, 20.2, 28.6, 40.2, 60.1,70.1, 80.1, 109.5, 126.0, 139.7, 143.6, 154.9. HRMS Calcd. forC₁₄H₂₁NO₄Na [M⁺+Na]: 290.1368.

[0772] Found: 290.1368.

[0773] General procedure for alkylation reactions (88-103). To a stirredsuspension of sodium hydride (1.3 eq., 60% suspension in mineral oil) indimethylformamide (8 mL) at 0° C. was added the alcohol 5 (usually 0.10g, 0.4 mmol). Following stirring under inert atmosphere at roomtemperature for 1 h benzyl bromide (3 eq.) was added. The reactionmixture was heated to 40° C. and stirred under inert atmosphere for 48h. To the reaction mixture was added ethyl acetate (40 mL) and water (20mL). The layers were separated and the organic layer dried overanhydrous magnesium sulfate, and concentrated in vacuo. Purification byflash column chromatography (hexanes/EtOAc 5:1) yielded pure products88-103 (Table 1). TABLE 1 Yields and product characterization for thealkylation reaction. % Calcd. Found # Name Yield HRMS HRMS 883-Benzyloxy-4-furan-3-yl- 41 380.1838 380.1840 piperidine-1-carboxylicacid [M⁺ + Na] tert-butyl ester 89 3-(Biphenyl-4-ylmethoxy)-4- 43456.2151 456.2146 furan-3-yl-piperidine-1- [M⁺ + Na] carboxylic acidtert-butyl ester 90 4-Furan-3-yl-3-(naphthalen- 6 430.1994 430.20942-ylmethoxy)-piperidine-1- [M⁺ + Na] carboxylic acid tert-butyl ester 914-Furan-3-yl-3-(naphthalen- 43 430.1994 430.19881-ylmethoxy)-piperidine-1- [M⁺ + Na] carboxylic acid tert-butyl ester 924-Furan-3-yl-3-(4-phenoxy- 56 472.2100 472.2110 benzyloxy)-piperidine-1-[M⁺ + Na] carboxylic acid tert-butyl ester 933-(4-tert-Butyl-benzyloxy)- 68 436.2464 436.24644-furan-3-yl-piperidine-1- [M⁺ + Na] carboxylic acid tert-butyl ester 943-(Anthracen-9-ylmethoxy)-4- 29 480.2151 480.2159furan-3-yl-piperidine-1- [M⁺ + Na] carboxylic acid tert-butyl ester 954-Furan-3-yl-3-(3-methyl- 74 394.1994 394.2002 benzyloxy)-piperidine-1-[M⁺ + Na] carboxylic acid tert-butyl ester 963-(3,5-Dimethoxy-benzyloxy)- 59 440.2049 440.2053 4-furan-3-yl- [M⁺ +Na] piperidine-1-carboxylic acid tert-butyl ester 973-(4-Bromo-benzyloxy)-4- 66 458.0943 458.0966 furan-3-yl-piperidine-1-[M⁺ + Na] carboxylic acid tert-butyl ester 98 4-Furan-3-yl-3-(4- 32458.1613 458.1633 methanesulfonyl-benzyloxy)- [M⁺ + Na]piperidine-1-carboxylic acid tert-butyl ester 994-Furan-3-yl-3-(2-methyl- 38 344.1838 344.1831 allyloxy)-piperidine-1-[M⁺ + Na] carboxylic acid tert-butyl ester 1003-Cyclohexylmethoxy-4-furan- 4 386.2307 386.23063-yl-piperidine-1-carboxylic [M⁺ + Na] acid tert-butyl ester 1013-(2-Cyclohexyl-ethoxy)-4- 41 400.2461 400.2455 furan-3-yl-piperidine-1-[M⁺ + Na] carboxylic acid tert-butyl ester 102 4-Furan-3-yl-3-isobutoxy-9 346.1994 346.1981 piperidine-1-carboxylic acid [M⁺ + Na] tert-butylester 103 3-(2-Ethyl-butoxy)-4-furan- 4 374.2307 374.23043-yl-piperidine-1-carboxylic [M⁺ + Na] acid tert-butyl ester

[0774] General procedure for ^(t)Boc removal reaction (104-118). To88-103 (usually 0.05 g) was added 4N HCl-dioxane (3 mL). The reactionmixture was stirred under inert atmosphere at room temperature for 30min. Removal of solvent at reduced pressure followed by trituration withdiethyl ether yielded pure products 104-118 (Table 2). TABLE 2 Yieldsand product characterization for the ^(t)Boc deprotection reaction. %Calcd. Found # Name Yield HRMS HRMS 104 3-Benzyloxy-4-furan-3-yl- 85280.1313 280.1316 piperidine [M⁺ + Na] 105 3-(Biphenyl-4-ylmethoxy)-4-98 334.1807 334.1806 furan-3-yl-piperidine [M⁺ + H] 1064-Furan-3-yl-3-(naphthalen- 99 330.1470 330.1463 2-ylmethoxy)-piperidine[M⁺ + Na] 107 4-Furan-3-yl-3-(naphthalen- 99 308.1650 308.16511-ylmethoxy)-piperidine [M⁺ + H] 108 4-Furan-3-yl-3-(4-phenoxy- 99350.1756 350.1767 benzyloxy)-piperidine [M⁺ + H] 1093-(4-tert-Butyl-benzyloxy)- 89 314.2120 314.2125 4-furan-3-yl-piperidine[M⁺ + H] 110 3-(Anthracen-9-ylmethoxy)-4- 52 358.1807 358.1815furan-3-yl-piperidine [M⁺ + H] 111 4-Furan-3-yl-3-(3-methyl- 99 272.1650272.1639 benzyloxy)-piperidine [M⁺ + H] 112 3-(3,5-Dimethoxy-benzyloxy)-99 318.1705 318.1703 4-furan-3-yl-piperidine [M⁺ + H] 1133-(4-Bromo-benzyloxy)-4- 99 336.0599 336.0610 furan-3-yl-piperidine[M⁺ + H] 114 4-Furan-3-yl-3-(2-methyl- 98 222.1494 222.1498allyloxy)-piperidine [M⁺ + H] 115 3-Cyclohexylmethoxy-4-furan- 99264.1963 264.1950 3-yl-piperidine [M⁺ + H] 1163-(2-Cyclohexyl-ethoxy)-4- 58 278.2120 278.2126 furan-3-yl-piperidine[M⁺ + H] 117 4-Furan-3-yl-3-isobutoxy- 73 224.1650 224.1658 piperidine[M⁺ + H] 118 3-(2-Ethyl-butoxy)-4-furan- 93 252.1964 3-yl-piperidine[M⁺ + H]

[0775] Examples for alkylation and ^(t)Boc Deprotection Reactions:

[0776] 3-Benzyloxy-4-furan-3-yl-piperidine-1-carboxylic acid tert-butylester (88). To a stirred suspension of sodium hydride (0.02 g, 0.5 mmol,1.3 eq., 60% suspension in mineral oil) in dimethylformamide (8 mL) at0° C. was added the alcohol 5 (0.10 g, 0.4 mmol). Following stirringunder inert atmosphere at room temperature for 1 h benzyl bromide (0.13mL, 1.1 mmol, 3 eq.) was added. The reaction mixture was heated to 40°C. and stirred under inert atmosphere for 48 h. To the reaction mixturewas added ethyl acetate (40 mL) and water (20 mL). The layers wereseparated and the organic layer dried over anhydrous magnesium sulfate,and concentrated in vacuo. Purification by flash column chromatography(hexanes/EtOAc 5:1) yielded clear viscous liquid 6 (0.05 g, 41%). TLCR_(f)=0.22; 400 MHz ¹H-NMR (CDCl₃) δ 1.47 (S, 9H), 1.62 (ddd, J=16.8,12.4, 4.4 Hz, 1H), 1.89 (m, 1H), 2.66 (m, 2H), 2.79 (t, J=12.4 Hz, 1H),3.25 (s, 1H), 4.06 (m, 1H), 4.38 (d, J=11.2 Hz, 2H), 4.53 (s, 1H), 6.33(s, 1H), 7.19 (d, J=7.2 Hz, 2H), 7.27 (m, 4H), 7.37 (s, 1H); 125 MHz¹³C-NMR (CDCl₃) δ 28.6, 39.5, 72.1, 78.1, 78.0, 110.2, 126.5, 127.8,128.0, 129.0, 138.3, 139.4, 142.8. HRMS Calcd. for C₂₁H₂₇NO₄Na [M⁺+Na]380.1838. Found: 380.1840.

[0777] 3-(Biphenyl-4-ylmethoxy)-4-furan-3-yl-piperidine-1-carboxylicacid tert-butyl ester (89). Clear viscous liquid (43%). TLC R_(f)=0.21;400 MHz ¹H-NMR (CDCl₃) δ 1.47 (s, 9H), 1.64 (m, 1H), 1.89 (m, 1H), 2.66(m, 2H), 2.80 (t, J=12.0 Hz, 1H), 3.29 (s, 1H), 4.06 (m, 1H), 4.42 (d,J=11.2 Hz, 2H), 4.57 (s, 1H), 6.35 (s, 1H), 7.27 (m, 2H), 7.33 (m, 2H),7.38 (m, 1H), 7.42 (m, 2H), 7.56 (m, 4H); 125 MHz ¹³C-NMR (CDCl₃) δ28.6, 39.5, 71.9, 78.2, 80.0, 110.3, 126.5, 127.2, 127.3, 127.4, 128.4,128.9.4, 137.3, 139.4, 140.8, 141.0, 142.8, 154.8. HRMS Calcd. forC₂₇H₃₁NO₄Na [M⁺+Na]: 456.2151. Found: 456.2146.

[0778] 4-Furan-3-yl-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylicacid tert-butyl ester (90). Clear viscous liquid (6%). TLC Rf=0.27; 400MHz ¹H-NMR (CDCl₃) δ 1.44 (s, 9H), 1.63 (m, 1H), 1.89 (m, 1H), 2.69 (m,2H), 2.80 (m, 1H), 3.30 (s, 1H), 4.09 (m, 1H), 4.54 (d, J=11.6 Hz, 2H),4.68 (m, 1H), 6.33 (s, 1H), 7.25 (m, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.32(m, 2H), 7.62 (s, 1H), 7.78 (m, 3H); 125 MHz ¹³C-NMR (CDCl₃) δ 28.6,39.6, 72.2, 78.2, 80.0, 110.3, 125.9, 126.0, 126.2, 126.5, 126.6, 127.8,128.1, 128.3, 133.2, 133.4, 135.8, 139.5, 142.8. HRMS Calcd. forC₂₅H₂₉NO₄Na [M⁺+Na]: 430.1994. Found: 430.2094.

[0779] 4-Furan-3-yl-3-(naphthalen-1-ylmethoxy)-piperidine-1-carboxylicacid tert-butyl ester (91). Clear viscous liquid (43%). TLC Rf=0.12; 400MHz ¹H-NMR (CDCl₃) δ 1.46 (s, 9H), 1.63 (m, 1H), 1.86 (m, 1H), 2.65 (m,2H), 2.77 (m, 1H), 3.36 (s, 1H), 4.06 (m, 1H), 4.51-5.12 (m, 3H), 6.26(s, 1H), 7.27 (d, J=27.2 Hz, 2H), 7.40 (m, 3H), 7.78 (m, 4H); 125 MHz¹³C-NMR (CDCl₃) δ 28.6, 39.5, 70.7, 78.1, 80.0, 109.9, 124.3, 125.3,125.9, 126.2, 126.4, 126.9, 128.5, 129.0, 131.9, 133.6, 133.9, 139.5,142.8. HRMS Calcd. for C₂₅H₂₉NO₄Na [M⁺+Na] 430.1994. Found: 430.1988.

[0780] 4-Furan-3-yl-3-(4-phenoxy-benzyloxy)-piperidine-1-carboxylic acidtert-butyl ester (92). Clear viscous liquid (56%). TLC R_(f)=0.16; 400MHz ¹H-NMR (CDCl₃) δ 1.46 (s, 9H), 1.61 (m, 1H), 1.85 (m, 1H), 2.62 (m,2H), 2.78 (t, J=12 Hz, 1H), 3.23 (m, 1H), 4.04 (m, 1H), 4.33 (d, J=11.6Hz, 2H), 4.51 (m, 1H), 6.28 (s, 1H), 6.89 (m, 3H), 6.99 (m, 2H), 7.09(t, J=7.2 Hz, 1H), 7.28 (m, 5H); 125 MHz ¹³C-NMR (CDCl₃) δ 28.6, 39.4,71.6, 78.4, 80.0, 110.2, 118.1, 119.0, 122.5, 123.4, 126.4, 129.7,129.9, 139.3, 140.4, 142.8, 154.7, 157.3, 157.5. HRMS Calcd. forC₂₇H₃₁NO₅Na [M⁺+Na]: 472.2100. Found: 472.2110.

[0781] 3-(4-tert-Butyl-benzyloxy)-4-furan-3-yl-piperidine-1-carboxylicacid tert-butyl ester (93). Clear viscous liquid (68%). TLC Rf=0.21; 400MHz ¹H-NMR (CDCl₃) δ 1.32 (s, 9H), 1.49 (s, 9H), 1.64 (ddd, J=16.8,12.4, 4.4 Hz, 1H), 1.90 (m, 1H), 2.66 (m, 2H), 2.80 (t, J=12.4 Hz, 1H),3.27 (s, 1H), 4.09 (m, 1H), 4.36 (d, J=10.8 Hz, 2H), 4.52 (m, 1H), 6.36(s, 1H), 7.15 (d, J=8.0 Hz, 2H), 7.33 (m, 3H), 7.38 (t, J=1.6 Hz, 1H);125 MHz ¹³C-NMR (CDCl₃) δ 14.3, 22.8, 28.6, 31.5, 34.7, 39.5, 72.0,78.1, 80.0, 110.2, 125.4, 126.5, 127.8, 135.2, 139.4, 142.7, 150.763,154.8. HRMS Calcd. for C₂₅H₃₅NO₄Na [M⁺+Na]: 436.2464. Found: 436.2464.

[0782] 3-Benzyloxy-4-furan-3-yl-piperidine (104). To 6 (0.07 g , 0.2mmol) was added 4N HCl-dioxane (4 mL). The reaction mixture was stirredunder inert atmosphere for 30 min. Removal of solvent at reducedpressure followed by trituration with diethyl ether yielded pure,crystaline 22 (0.05 g, 85%); 400 MHz ¹H-NMR (CD₃OD) δ 2.02 (m, 1H), 2.22(m, 1H), 2.99 (m, 2H), 3.12 (m, 1H), 3.60 (m, 0.5H), 3.68 (m, 1H), 3.75(m, 0.5H), 3.82 (td, J 8.4, 3.6 Hz, 1H), 4.60 (d, J=11.2 Hz, 1H), 4.51(d, J=11.2 Hz, 1H), 6.46 (s, 1H), 7.30 (m, 5H), 7.49 (m, 2H); 125 MHz¹³C-NMR (CD₃OD) δ 27.4, 37.2, 43.8, 46.8, 73.9, 75.8, 104.2, 110.9,129.1, 129.2, 129.5, 139.2, 141.2, 144.6. HRMS Calcd. for C₁₆H₁₉NO₂Na[M⁺+Na]: 280.1313. Found: 280.1316.

[0783] 3-(Biphenyl-4-ylmethoxy)-4-furan-3-yl-piperidine (105). Solid(98%); 400 MHz ¹H-NMR (CD₃OD) δ 2.02 (m, 1H), 2.22 (m, 1H), 2.99 (m,2H), 3.11 (m, 1H), 3.59 (m, 0.5H), 3.66 (m, 1H), 3.74 (m, 0.5H), 3.82(td, J=8.0, 3.2 Hz, 1H), 4.54 (d, J=11.6 Hz, 1H), 4.62 (d, J=11.6 Hz,1H), 6.46 (s, 1H), 7.34 (m, 2H), 7.43 (m, 3H); 7.49 (m, 2H), 7.58 (m,4H); 125 MHz ¹³C-NMR (CD₃OD) δ 27.4, 37.2, 43.8, 46.8, 73.1, 75.8,110.9, 128.0, 128.1, 128.6, 129.8, 130.0, 141.2, 144.7. HRMS Calcd. forC₂₂H₂₄NO₂ [M⁺+H]: 334.1807. Found: 334.1806.

[0784] 4-Furan-3-yl-3-(naphthalen-2-ylmethoxy)-piperidine(106). Solid(99%); 400 MHz ¹H-NMR (CD₃OD) δ 1.99 (m, 1H), 2.24 (m, 1H), 3.03 (m,2H), 3.11 (m, 1H), 3.59 (m, 0.5H), 3.67 (m, 1H), 3.75 (m, 0.5H), 3.83(td, J=8.0, 3.2 Hz, 1H), 4.69 (d, J=11.6 Hz, 1H), 4.76 (d, J=11.6 Hz,1H), 6.44 (s, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.49 (m, 4H); 7.74 (s, 1H),7.83 (m, 3H); 125 MHz ¹³C-NMR (CD₃OD) δ 27.3, 37.1, 43.8, 46.9, 68.2,73.4, 110.8, 127.0, 127.2, 127.9, 128.7, 129.0, 129.2, 134.7, 141.2,144.6. HRMS Calcd. for C₂₀H₂₁NO₂ [M⁺+Na]: 330.1470. Found: 330.1463.

[0785] 4-Furan-3-yl-3-(naphthalen-1-ylmethoxy)-piperidine(107). Solid(99%); 400 MHz ¹H-NMR (CD₃OD) δ 1.98 (m, 1H), 2.12 (m, 1H), 2.91 (m,2H), 3.03 (m, 1H), 3.46 (m, 1H), 3.63 (s, 1H), 3.86 (m, 1H), 4.91 (d,J=11.6 Hz, 1H), 4.96 (d, J=11.6 Hz, 1H), 6.36 (s, 1H), 7.42 (m, 5H),7.84 (m, 3H); 125 MHz ¹³C-NMR (CD₃OD) δ 27.8, 37.4, 43.9, 47.0, 68.2,71.9, 75.7, 110.6, 125.3, 126.3, 127.0, 127.3, 128.4, 130.0, 130.2,134.4, 135.3, 141.3, 144.6. HRMS Calcd. for C₂₀H₂₁NO₂ [M⁺+H]: 308.1650.Found: 308. 1651.

[0786] 4-Furan-3-yl-3-(4-phenoxy-benzyloxy)-piperidine(108). Solid(99%); 400 MHz ¹H-NMR (CD₃OD) δ 1.99 (m, 1H), 2.17 (m, 1H), 2.96 (m,2H), 3.08 (m, 1H), 3.49 (m, 1H), 3.65 (s, 1H), 3.78 (m, 1H), 4.45 (d,J=11.6 Hz, 1H), 4.57 (d, J=11.6 Hz, 1H), 6.39 (s, 1H), 6.95 (m, 5H),7.10 (t, J=7.2 Hz, 1H), 7.32 (m, 4H), 7.42 (s, 1H); 125 MHz ¹³C-NMR(CD₃OD) δ 27.4, 37.2, 43.9, 46.8, 72.9, 76.0, 110.8, 119.2, 119.3,120.0, 123.8, 124.6, 125.9, 130.7, 131.0, 141.2, 141.3, 144.6, 158.6,159.0. HRMS Calcd. for C₂₂H₂₄NO₃ [M⁺+H]: 350.1756. Found: 350.1767.

[0787] 3-(4-tert-Butyl-benzyloxy)-4-furan-3-yl-piperidine(109). Solid(89%); 400 MHz ¹H-NMR (CD₃OD) δ 1.99 (m, 1H), 2.23 (m, 1H), 2.98 (m,2H), 3.10 (m, 1H), 3.45 (m, 1H), 3.67 (s, 1H), 3.78 (m, 1H), 4.49 (d,J=11.6 Hz, 1H), 4.55 (d, J=11.6 Hz, 1H), 6.43 (s, 1H), 7.20 (d, J=8.0Hz, 2H), 7.37 (d, J=8 Hz, 4H), 7.47 (d, J=15.6 Hz, 1H); 125 MHz ¹³C-NMR(CD₃OD) δ 27.3, 31.9, 35.5, 37.1, 43.8, 46.9, 68.3, 73.2, 75.5, 110.9,126.0, 126.4, 129.2, 136.1, 141.2, 144.7, 152.3. HRMS Calcd. forC₂₀H₂₈NO₂ [M⁺+H]: 314.2120. Found: 314.2125.

Table of Compounds

[0788] Products of alkylation reactions (88-103)

3-Benzyloxy-4-furan-3-yl- 3-(Biphenyl-4-ylmethoxy)-4-Furan-3-yl-3-(naphthalen- piperidine-1-carboxylic4-furan-3-yl-piperidine-1- 2-ylmethoxy)-piperidine-1- acid tert-butylester, 88, carboxylic acid tert-butyl ester, 89, carboxylic acidtert-butyl ester, 90, Exact Mass: 357.1940 Exact Mass: 433.2253 ExactMass: 407.2097

4-Furan-3-yl-3-(naphthalen-1- 4-Furan-3-yl-3-(4-phenoxy-3-(4-tert-Butyl-benzyloxy)-4- ylmethoxy)-piperidine-1-benzyloxy)-piperidine-1- furan-3-yl-piperidine-1- carboxylic acidtert-butyl ester, 91, carboxylic acid tert-butyl ester, 92, carboxylicacid tert-butyl ester, 93, Exact Mass: 407.2097 Exact Mass: 449.2202Exact Mass: 313.2042

3-(Anthracen-9-ylmethoxy)- 4-Furan-3-yl-3-(3-methyl-3-(3,5-Dimethoxy-benzyloxy)- 4-furan-3-yl-piperidine-1-benzyloxy)-piperidine-1- 4-furan-3-yl-piperidine-1- carboxylic acidtert-butyl ester, 94, carboxylic acid tert-butyl ester, 95, carboxylicacid tert-butyl ester, 96, Exact Mass: 457.2253 Exact Mass: 371.2097Exact Mass: 417.2151

3-(4-Bromo-benzyloxy)-4-furan- 4-Furan-3-yl-3-(4-methane4-Furan-3-yl-3-(2-methyl-allyloxy)- 3-yl-piperidine-1-carboxylicsulfonyl-benzyloxy)-piperidine- piperidine-1-carboxylic acid acidtert-butyl ester, 97, 1-carboxylic acid tert-butyl ester, 98, tert-butylester, 99, Exact Mass: 435.1045 Exact Mass: 435.1716 Exact Mass:321.1940

3-Cyclohexylmethoxy-4- 3-(2-Cyclohexyl-ethoxy)-4-Furan-3-yl-3-isobutoxy- furan-3-yl-piperidine-1-4-furan-3-yl-piperidine-1- piperidine-1-carboxylic carboxylic acidtert-butyl ester, 100, carboxylic acid tert-butyl ester, 101, acidtert-butyl ester, 102, Exact Mass: 363.2410 Exact Mass: 377.2566 ExactMass: 323.2097

3-(2-Ethyl-butoxy)-4-furan- 3-yl-piperidine-1-carboxylic acid tert-butylester, 103, Exact Mass: 351.4804 Products of ^(t)Boc deprotectionreactions (104-118)

3-Benzyloxy-4-furan-3- 3-(Biphenyl-4-ylmethoxy)-4-4-Furan-3-yl-3-(naphthalen-2- yl-piperidine, 104, furan-3-yl-piperidine,105, ylmethoxy)-piperidine, 106, Exact Mass: 257.1416 Exact Mass:333.1729 Exact Mass: 307.1572

4-Furan-3-yl-3-(naphthalen-1- 4-Furan-3-yl-3-(4-phenoxy-3-(4-tert-Butyl-benzyloxy)-4- ylmethoxy)-piperidine, 107,benzyloxy)piperidine, 108, furan-3-yl-piperidine, 109, Exact Mass:307.1572 Exact Mass: 349.1678 Exact Mass: 313.2042

3-(Anthracen-9-ylmethoxy)-4- 4-Furan-3-yl-3-(3-methyl-3-(3,5-Dimethoxy-benzyloxy)-4- furan-3-yl-piperidine, 110,benzyloxy)-piperidine, 111, furan-3-yl-piperidine, 112, Exact Mass:357.1729 Exact Mass: 271.1572 Exact Mass: 317.1627

3-(4-Bromo-benzyloxy)-4- 4-Furan-3-yl-3-(2-methyl-3-Cyclohexylmethoxy-4-furan-3- furan-3-yl-piperidine, 113,allyloxy)-piperidine, 114, yl-piperidine, 115, Exact Mass: 335.0521Exact Mass: 221.1416 Exact Mass: 263.1885

3-(2-Cyclohexyl-ethoxy)-4- 4-Furan-3-yl-3-isobutoxy-3-(2-Ethyl-butoxy)-4-furan-3- furan-3-yl-piperidine, 116, piperidine,117 yl-piperidine, 118, Exact Mass: 277.2042 Exact Mass: 223.1572 ExactMass: 251.1885

BIOLOGY EXAMPLES

[0789] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, practice the invention toits fullest extent. The invention, however, may be better understoodwith reference to the following examples. These examples are intended tobe representative of specific embodiments of the invention, and are notintended as limiting the scope of the invention.

EXAMPLE A

[0790] Enzyme Inhibition Assay

[0791] The compounds of the invention are analyzed for inhibitoryactivity by use of the MBP-C125 assay. This assay determines therelative inhibition of beta-secretase cleavage of a model APP substrate,MBP-C125SW, by the compounds assayed as compared with an untreatedcontrol. A detailed description of the assay parameters can be found,for example, in U.S. Pat. No. 5,942,400. Briefly, the substrate is afusion peptide formed of maltose binding protein (MBP) and the carboxyterminal 125 amino acids of APP-SW, the Swedish mutation. Thebeta-secretase enzyme is derived from human brain tissue as described inSinha et al, 1999, Nature 40:537-540) or recombinantly produced as thefull-length enzyme (amino acids 1-501), and can be prepared, forexample, from 293 cells expressing the recombinant cDNA, as described inWO00/47618.

[0792] Inhibition of the enzyme is analyzed, for example, by immunoassayof the enzyme's cleavage products. One exemplary ELISA uses an anti-MBPcapture antibody that is deposited on precoated and blocked 96-well highbinding plates, followed by incubation with diluted enzyme reactionsupernatant, incubation with a specific reporter antibody, for example,biotinylated anti-SW192 reporter antibody, and further incubation withstreptavidin/alkaline phosphatase. In the assay, cleavage of the intactMBP-C125SW fusion protein results in the generation of a truncatedamino-terminal fragment, exposing a new SW-192 antibody-positive epitopeat the carboxy terminus. Detection is effected by a fluorescentsubstrate signal on cleavage by the phosphatase. ELISA only detectscleavage following Leu 596 at the substrate's APP-SW 751 mutation site.

[0793] Specific Assay Procedure

[0794] Compounds are diluted in a 1:1 dilution series to a six-pointconcentration curve (two wells per concentration) in one 96-plate rowper compound tested. Each of the test compounds is prepared in DMSO tomake up a 10 millimolar stock solution. The stock solution is seriallydiluted in DMSO to obtain a final compound concentration of 200micromolar at the high point of a 6-point dilution curve. Ten (10)microliters of each dilution is added to each of two wells on row C of acorresponding V-bottom plate to which 190 microliters of 52 millimolarNaOAc, 7.9% DMSO, pH 4.5 are pre-added. The NaOAc diluted compound plateis spun down to pellet precipitant and 20 microliters/well istransferred to a corresponding flat-bottom plate to which 30 microlitersof ice-cold enzyme-substrate mixture (2.5 microliters MBP-C125SWsubstrate, 0.03 microliters enzyme and 24.5 microliters ice cold 0.09%TX100 per 30 microliters) is added. The final reaction mixture of 200micromolar compound at the highest curve point is in 5% DMSO, 20millimolar NaOAc, 0.06% TX100, at pH 4.5.

[0795] Warming the plates to 37 degrees C. starts the enzyme reaction.After 90 minutes at 37 degrees C., 200 microliters/well cold specimendiluent is added to stop the reaction and 20 microliters/well wastransferred to a corresponding anti-MBP antibody coated ELISA plate forcapture, containing 80 microliters/well specimen diluent. This reactionis incubated overnight at 4 degrees C. and the ELISA is developed thenext day after a 2 hour incubation with anti-192SW antibody, followed byStreptavidin-AP conjugate and fluorescent substrate. The signal is readon a fluorescent plate reader.

[0796] Relative compound inhibition potency is determined by calculatingthe concentration of compound that showed a fifty percent reduction indetected signal (IC₅₀) compared to the enzyme reaction signal in thecontrol wells with no added compound. In this assay, the compounds ofthe invention exhibited an IC50 of less than 50 micromolar.

EXAMPLE B

[0797] Cell Free Inhibition Assay Utilizing a Synthetic APP Substrate

[0798] A synthetic APP substrate that can be cleaved by beta-secretaseand having N-terminal biotin and made fluorescent by the covalentattachment of Oregon green at the Cys residue is used to assaybeta-secretase activity in the presence or absence of the inhibitorycompounds of the invention. Useful substrates include the following:[SEQ ID NO: 1] Biotin-SEVNL-DAEFR[Oregon green]KK [SEQ ID NO: 2]Biotin-SEVKM-DAEFR[Oregon green]KK [SEQ ID NO: 3]Biotin-GLNIKTEEISEISY-EVEFRC [Oregon green]KK [SEQ ID NO: 4]Biotin-ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF Oregon green]KK [SEQ ID NO: 5]Biotin-FVNQHLCoxGSHLVEALY-LVCoxGERGFFYTPKA [Oregon green]KK

[0799] The enzyme (0.1 nanomolar) and test compounds (0.001-100micromolar) are incubated in pre-blocked, low affinity, black plates(384 well) at 37 degrees for 30 minutes. The reaction is initiated byaddition of 150 millimolar substrate to a final volume of 30 microliterper well. The final assay conditions are: 0.0014-100 micromolar compoundinhibitor; 0.1 molar sodium acetate (pH 4.5); 150 nanomolar substrate;0.1 nanomolar soluble beta-secretase; 0.001% Tween 20, and 2% DMSO. Theassay mixture is incubated for 3 hours at 37 degrees C., and thereaction is terminated by the addition of a saturating concentration ofimmunopure streptavidin. After incubation with streptavidin at roomtemperature for 15 minutes, fluorescence polarization is measured, forexample, using a LJL Acqurest (Ex485 nm/Em530 nm). The activity of thebeta-secretase enzyme is detected by changes in the fluorescencepolarization that occur when the substrate is cleaved by the enzyme.Incubation in the presence or absence of compound inhibitor demonstratesspecific inhibition of beta-secretase enzymatic cleavage of itssynthetic APP substrate. In this assay, compounds of the inventionexhibited an IC50 of less than 50 micromolar.

EXAMPLE C

[0800] Beta-Secretase Inhibition: P26-P4′SW Assay

[0801] Synthetic substrates containing the beta-secretase cleavage siteof APP are used to assay beta-secretase activity, using the methodsdescribed, for example, in published PCT application WO00/47618. TheP26-P4SW substrate is a peptide of the sequence: The P-26-P4′SWsubstrate is a peptide of the sequence: [SEQ ID NO: 6] (biotin)CGGADRGLTTRPGSGLTNIKTEETSEVNLDAEF The P26-P1 standard has the sequence:[SEQ ID NO: 7] (biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNL.

[0802] Briefly, the biotin-coupled synthetic substrates are incubated ata concentration of from about 0 to about 200 micromolar in this assay.When testing inhibitory compounds, a substrate concentration of about1.0 micromolar is preferred. Test compounds diluted in DMSO are added tothe reaction mixture, with a final DMSO concentration of 5%. Controlsalso contain a final DMSO concentration of 5%. The concentration of betasecretase enzyme in the reaction is varied, to give productconcentrations with the linear range of the ELISA assay, about 125 to2000 picomolar, after dilution.

[0803] The reaction mixture also includes 20 millimolar sodium acetate,pH 4.5, 0.06% Triton X100, and is incubated at 37 degrees C. for about 1to 3 hours. Samples are then diluted in assay buffer (for example, 145.4nanomolar sodium chloride, 9.51 millimolar sodium phosphate, 7.7millimolar sodium azide, 0.05% Triton X405, 6 g/liter bovine serumalbumin, pH 7.4) to quench the reaction, then diluted further forimmunoassay of the cleavage products.

[0804] Cleavage products can be assayed by ELISA. Diluted samples andstandards are incubated in assay plates coated with capture antibody,for example, SW192, for about 24 hours at 4 degrees C. After washing inTTBS buffer (150 millimolar sodium chloride, 25 millimolar Tris, 0.05%Tween 20, pH 7.5), the samples are incubated with streptavidin-APaccording to the manufacturer's instructions. After a one hourincubation at room temperature, the samples are washed in TTBS andincubated with fluorescent substrate solution A (31.2 g/liter2-amino-2-methyl-1-propanol, 30 mg/liter, pH 9.5). Reaction withstreptavidin-alkaline phosphate permits detection by fluorescence.Compounds that are effective inhibitors of beta-secretase activitydemonstrate reduced cleavage of the substrate as compared to a control.

EXAMPLE D

[0805] Assays Using Synthetic Oligopeptide-Substrates

[0806] Synthetic oligopeptides are prepared that incorporate the knowncleavage site of beta-secretase, and optionally detectable tags, such asfluorescent or chromogenic moieties. Examples of such peptides, as wellas their production and detection methods are described in U.S. Pat. No.5,942,400, herein incorporated by reference. Cleavage products can bedetected using high performance liquid chromatography, or fluorescent orchromogenic detection methods appropriate to the peptide to be detected,according to methods well known in the art.

[0807] By way of example, one such peptide has the sequence SEVNL-DAEF[SEQ ID NO: 8], and the cleavage site is between residues 5 and 6.Another preferred substrate has the sequenceADRGLTTRPGSGLTNIKTEEISEVNL-DAEF [SEQ ID NO: 9], and the cleavage site isbetween residues 26 and 27.

[0808] These synthetic APP substrates are incubated in the presence ofbeta-secretase under conditions sufficient to result in beta-secretasemediated cleavage of the substrate. Comparison of the cleavage resultsin the presence of the compound inhibitor to control results provides ameasure of the compound's inhibitory activity.

EXAMPLE E

[0809] Inhibition of Beta-Secretase Activity—Cellular Assay

[0810] An exemplary assay for the analysis of inhibition ofbeta-secretase activity utilizes the human embryonic kidney cell lineHEKp293 (ATCC Accession No. CRL-1573) transfected with APP751 containingthe naturally occurring double mutation Lys651Met52 to Asn651Leu652(numbered for APP751), commonly called the Swedish mutation and shown tooverproduce A beta (Citron et al., 1992, Nature 360:672-674), asdescribed in U.S. Pat. No. 5,604,102.

[0811] The cells are incubated in the presence/absence of the inhibitorycompound (diluted in DMSO) at the desired concentration, generally up to10 micrograms/ml. At the end of the treatment period, conditioned mediais analyzed for beta-secretase activity, for example, by analysis ofcleavage fragments. A beta can be analyzed by immunoassay, usingspecific detection antibodies. The enzymatic activity is measured in thepresence and absence of the compound inhibitors to demonstrate specificinhibition of beta-secretase mediated cleavage of APP substrate.

EXAMPLE F

[0812] Inhibition of Beta-Secretase in Animal Models of AD

[0813] Various animal models can be used to screen for inhibition ofbeta-secretase activity. Examples of animal models useful in theinvention include, but are not limited to, mouse, guinea pig, dog, andthe like. The animals used can be wild type, transgenic, or knockoutmodels. In addition, mammalian models can express mutations in APP, suchas APP695-SW and the like described herein. Examples of transgenicnon-human mammalian models are described in U.S. Pat. Nos. 5,604,102,5,912,410 and 5,811,633.

[0814] PDAPP mice, prepared as described in Games et al., 1995, Nature373:523-527 are useful to analyze in vivo suppression of A beta releasein the presence of putative inhibitory compounds. As described in U.S.Pat. No. 6,191,166, 4 month old PDAPP mice are administered compoundformulated in vehicle, such as corn oil. The mice are dosed withcompound (1-30 mg/ml; preferably 1-10 mg/ml). After time, e.g., 3-10hours, the animals are sacrificed, and brains removed for analysis.

[0815] Transgenic animals are administered an amount of the compoundinhibitor formulated in a carrier suitable for the chosen mode ofadministration. Control animals are untreated, treated with vehicle, ortreated with an inactive compound. Administration can be acute, i.e.,single dose or multiple doses in one day, or can be chronic, i.e.,dosing is repeated daily for a period of days. Beginning at time 0,brain tissue or cerebral fluid is obtained from selected animals andanalyzed for the presence of APP cleavage peptides, including A beta,for example, by immunoassay using specific antibodies for A betadetection. At the end of the test period, animals are sacrificed andbrain tissue or cerebral fluid is analyzed for the presence of A betaand/or beta-amyloid plaques. The tissue is also analyzed for necrosis.

[0816] Animals administered the compound inhibitors of the invention areexpected to demonstrate reduced A beta in brain tissues or cerebralfluids and reduced beta amyloid plaques in brain tissue, as comparedwith non-treated controls.

EXAMPLE G

[0817] Inhibition of A Beta Production in Human Patients

[0818] Patients suffering from Alzheimer's Disease (AD) demonstrate anincreased amount of A beta in the brain. AD patients are administered anamount of the compound inhibitor formulated in a carrier suitable forthe chosen mode of administration. Administration is repeated daily forthe duration of the test period. Beginning on day 0, cognitive andmemory tests are performed, for example, once per month.

[0819] Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; A beta depositsin the brain; amyloid plaque in the brain; and scores for cognitive andmemory function, as compared with control, non-treated patients.

EXAMPLE H

[0820] Prevention of A Beta Production in Patients at Risk for AD

[0821] Patients predisposed or at risk for developing AD are identifiedeither by recognition of a familial inheritance pattern, for example,presence of the Swedish Mutation, and/or by monitoring diagnosticparameters. Patients identified as predisposed or at risk for developingAD are administered an amount of the compound inhibitor formulated in acarrier suitable for the chosen mode of administration. Administrationis repeated daily for the duration of the test period. Beginning on day0, cognitive and memory tests are performed, for example, once permonth.

[0822] Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; amyloid plaque inthe brain; and scores for cognitive and memory function, as comparedwith control, non-treated patients.

EXAMPLE H Biological Inhibition Activity

[0823] The biological activity of the compound prepared according toExample 29 was measured in accordance with the above describedprocedures

[0824] The invention has been described with reference to variousspecific and preferred embodiments and techniques. However, it should beunderstood that many variations and modifications may be made whileremaining within the spirit and scope of the invention.

What is claimed is:
 1. A compound of the formula I:

or a pharmaceutically acceptable salt or ester thereof, wherein Z is CHor N; wherein R₁ and R₃ are independently: (I) C₁-C₁₀ alkyl, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,—C—N, —CF₃, C₁-C₃ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are independently —H or C₁-C₆ alkyl, —OC═O NR_(1-a)R_(1-b),—S(═O)₀₋₂ R_(1-a), —NR_(1-a)C═O NR_(1-a)R_(1-b), —C═O NR_(1-a)R_(1-b),and —S(═O)₂ NR_(1-a)R_(1-b), —(CH₂)₀₋₃-(C₃-C₈) cycloalkyl wherecycloalkyl can be optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, —CO—OH,—CO—O—(C₁-C₄ alkyl), —NR_(1-a)R_(1-b); C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R₁-heteroaryl), (II) —(CH₂)_(n1)—(R_(1-aryl)) where n₁ is zeroor one and where R_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl andindanyl, indenyl, dihydronaphthyl, tetralinyl optionally substitutedwith one, two, three or four of the following independently selectedsubstituents on the aryl ring: (1) C₁-C₆ alkyl optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆alkyl), —S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆alkyl), —S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆alkyl), —SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl),—NR-aR_(1-b), —C—N, —CF₃, C₁-C₃ alkoxy, C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (2) C₂-C₆ alkenyl with one or two doublebonds, optionally substituted with one, two or three substituentsindependently selected from the group consisting of —F, —Cl, —Br, —I,—OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆alkyl), —C—N, —CF₃, C₁-C₃ alkoxy, —NR1 aR_(1-b), C₁-C₃alkoxy-(R_(1-a)ryl), C₁-C₃ alkoxy-(R₁-heteroaryl), (3) C₂-C₆ alkynylwith one or two triple bonds, optionally substituted with one, two orthree substituents independently selected from the group consisting of—F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b),C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R₁-heteroaryl), (4) —F, Cl, —Brand —I, (5) —C₁-C₆ alkoxy optionally substituted with one, two or three—F, (6) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined below,(7) —OH, (8) —C—N, (9) C₃-C₇ cycloalkyl, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b),C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (10) —CO—(C₁-C₄ alkyl), (11) —SO₂—NR_(1-a)R_(1-b), (12) —CO—NR_(1-a)R_(1-b), (13)—SO₂—(C₁-C₄ alkyl), (III) —(CH₂) 1—(R_(1-heteroaryl)) where n₁ is asdefined above and where R_(1-heteroaryl) is selected from the groupconsisting of: pyridinyl, pyrimidinyl, quinolinyl, benzothienyl,indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl,isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl,isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide, where theR_(1-heteroaryl) group is bonded to —(CH₂)_(n1)— by any ring atom of theparent R_(1-heteroaryl) group substituted by hydrogen such that the newbond to the R_(1-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is optionally substituted with one, two, three orfour of: (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —NR_(1-a)R_(1-b), —C≡N, —CF₃, C₁-C₃ alkoxy,C₁-C₃ alkoxy-(R1 aryl), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (2) C₂-C₆alkenyl with one or two double bonds, optionally substituted with one,two or three substituents independently selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆alkyl), —S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁-6alkyl), —S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₃ alkoxy,—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-a)ryl), C₁-C₃alkoxy-(R_(1-heteroaryl)), (3) C₂-C₆ alkynyl with one or two triplebonds, optionally substituted with one, two or three substituentsindependently selected from the group consisting of —F, —Cl, —Br, —I,—OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆alkyl), —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (4) —F, —Cl, —Brand —I, (5) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F, (6) —NR_(N-2)R_(N-3), (7) —OH, (8) —C≡N, (9) C₃-C₇ cycloalkyl,optionally substituted with one, two or three substituents independentlyselected from the group consisting of —F, —Cl, —Br, —I, —OH, —SH,—S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl),—S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl),—SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl),—C—N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)),C₁-C₃ alkoxy-(R_(1-heteroaryl)), (10) —CO— (C₁-C₄ alkyl), (11)—SO₂—NR_(1-a)R_(1-b), (12) —CO—NR_(1-a)R_(1-b), (13) —SO₂—(C₁-C₄ alkyl),with the proviso that when n₁ is zero, R_(1-heteroaryl) is not bonded tothe carbon chain by nitrogen, (IV) — (CH₂)_(n1)-(R_(1-heterocycle))where n₁ is as defined above and R_(1-heterocycle) is selected from thegroup consisting of:  morpholinyl, thiomorpholinyl, thiomorpholinylS-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl,pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl,tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl,homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl dihydropyrazinyl dihydropyridinyldihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienylS-oxide, tetrahydrothienyl S,S-dioxide, homothiomorpholinyl S-oxide,where the R_(1-heterocycle) group is bonded by any atom of the parentR_(1-heterocycle) group substituted by hydrogen such that the new bondto the R_(1-heterocycle) group replaces the hydrogen atom and its bond,where heterocycle is optionally substituted with one, two, three orfour: (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —NR_(1-a)R_(1-b), —C—N, —CF₃, C₁-C₃ alkoxy,C₁-C₃ alkoxy-(R₁ aryl), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (2) C₂-C₆alkenyl with one or two double bonds, optionally substituted with one,two or three substituents independently selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆alkyl), —S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆alkyl), —S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₃ alkoxy,—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (3) C₂-C₆ alkynyl with one or two triplebonds, optionally substituted with one, two or three substituentsindependently selected from the group consisting of —F, —Cl, —Br, —I,—OH—SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl),—S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl),—SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl),—C—N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R-aryl), C₁-C₃alkoxy-(R₁-heteroaryl), (4) —F, —Cl, —Br and —I, (5) —C₁-C₆ alkoxyoptionally substituted with one, two, or three —F, (6) —NR_(N-2)R_(N-3),(7) —OH, (8) —C—N, (9) C₃-C₇ cycloalkyl, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₃ alkoxy, —NR,aR_(1-b),C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (10) —CO—(C₁-C₄ alkyl), (11) —SO₂—NR_(1-a)R_(1-b), (12) —CO—NR_(1-a)R_(1-b), (13)—SO₂— (C₁-C₄ alkyl), (14) ═O, with the proviso that when n₁ is zeroR_(1-heterocycle) is not bonded to the carbon chain by nitrogen; (V) —H;(VI) R_(N-1)—X_(N)— where X_(N) is selected from the group consistingof: (A) —CO—, (B) —SO₂— where R_(N-1) is selected from the groupconsisting of: (A) R_(N-aryl) where R_(N-aryl) is phenyl, 1-naphthyl,2-naphthyl, tetralinyl, indanyl, dihydronaphthyl or6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, optionally substituted withone, two or three of the following substituents which can be the same ordifferent and are: (1) C₁-C₆ alkyl, optionally substituted with one, twoor three substituents selected from the group consisting of C₁-C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂ (C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂ (heteroaryl-C₁₋₆ alkyl), —CC—N, —CF₃, C₁-C₃ alkoxy,—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (2) —OH, (3) —NO₂, (4) —F, —Cl, —Br, —I, (5)—CO—OH, (6) —C≡N, (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) andR_(N-3) are the same or different and are selected from the groupconsisting of:  (a) —H,  (b) —C₁-C₆ alkyl optionally substituted withone substitutent selected from the group consisting of: (i) —OH, (ii)—NH₂,  (c) —C₁-C₆ alkyl optionally substituted with one to three groupsindependently selected from —F, —Cl, —Br, and —I,  (d) —C₃-C₇cycloalkyl,  (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),  (f) —(C₁-C₆alkyl)-O—(C₁-C₃ alkyl),  (9) —C₂-C₆ alkenyl with one or two doublebonds,  (h) —C₂—C₆ alkynyl with one or two triple bonds,  (i) —C₁-C₆hydrocarbyl chain with one double bond and one triple bond,  (j)—R_(1-aryl,)  (k) —R_(1-heteroaryl), (8) —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),(9) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one, two or three double bonds),(10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one, two or three triple bonds),(11) —(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl), (12) —(CH₂)₀₋₄—CO-R_(1-aryl),(13) —(CH₂)₀₋₄-CO—R_(1-heteroaryl), (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle),(15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from the groupconsisting of morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide,homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where eachgroup is optionally substituted with one, two, three, or four of C₁-C₆alkyl, (16) —(CH₂)₀₋₄-CO—O—R_(N-5) where R_(N-5) is selected from thegroup consisting of:  (a) C₁-C₆ alkyl,  (b) —(CH₂)₀₋₂-(R_(1-aryl)),  (c)C₂-C₆ alkenyl containing one or two double bonds,  (d) C₂-C₆ alkynylcontaining one or two triple bonds,  (e) C₃-C₇ cycloalkyl,  (f)—(CH₂)₀₋₂ (R_(1-heteroaryl)), (17) —(CH₂) O₄—SO₂—NRN₂R_(N-3), (18)—(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), (19) —(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl), (20)—(CH₂) O₄—SO₂— (C₃-C₇ cycloalkyl), (21) —(CH₂)₀₋₄—N(H orR_(N-5))—CO—O—R_(N-5) where R_(N-5) can be the same or different, (22)—(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, where each R_(N-5) isindependently defined herein, (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, whereeach R_(N-5) is independently defined herein, (24) —(CH₂)₀₋₄—N(—H orR_(N-5))—CO—R_(N-2), (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3), (26)—(CH₂)₀₋₄—R_(N-4), (27) —(CH₂)₀₋₄—O—CO— (C₁-C₆ alkyl), (28)—(CH₂)₀₋₄—O—P(O)—(OR_(N-1))₂ where R_(N-1) is —H or C₁-C₄ alkyl, (29)—(CH₂)₀₋₄—O—CO—N(R_(N-5))₂, (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂, (31)—(CH₂)₀₋₄-O— (R_(N-5))₂, (32) —(CH₂)₀₋₄-Q-(R_(N-5))₂-COOH, (33)—(CH₂)₀₋₄—S—(R_(N-5))₂, (34) —(CH₂)₀₋₄-O— (C₁-C₆ alkyl optionallysubstituted with one, two, three, four, or five of —F), (35) C₃-C₇cycloalkyl, (36) C₂-C₆ alkenyl having one or two double bonds and whichis optionally substituted with C₁-C₃ alkyl, —F, -Cl, —Br, —I, —OH, —SH,—S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl),—S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl),—SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl),—C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)),C₁-C₃ alkoxy-(R₁-heteroaryl), (37) C₂-C₆ alkynyl with one or two triplebonds optionally substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH,—SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl),—S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl),—SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl),—C—N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)),C₁-C₃ alkoxy-(R_(1-heteroaryl)), (38) —(CH₂)₀₋₄—N(—H orR_(N-5))—SO₂—R_(N-2), or (39) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (B)—R_(N-heteroaryl) where R_(N-heteroaryl) carries the same definition asRlheteroaryl, where the R_(N-heteroaryl) group is bonded by any atom ofthe parent R_(N-heteroaryl) group substituted by hydrogen such that thenew bond to the R_(N-heteroaryl) group replaces the hydrogen atom andits bond, where heteroaryl is optionally substituted with one, two,three, or four groups independently selected from: (1) C₁-C₆ alkyl,optionally substituted with one, two or three substituents selected fromthe group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆alkyl), —S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆alkyl), —S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl), —SO₂(C₁₋₆alkyl), —SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (2) —OH, (3) —NO₂, (4) —F, —Cl, —Br, —I, (5)—CO—OH, (6) —C—N, (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3), (C)R_(N-aryl)-W-R_(N-aryl), (D) R_(N-aryl)-W-R_(N-heteroaryl), (E)R_(N-aryl)-W-R_(N-heterocycle), where R_(N-heterocycle) is the same asR_(1-heterocycle) (F) R_(N-heteroaryl)-W-R_(N-aryl), (G)R_(N-heteroaryl)-W-R_(N-heteroaryl), (H)R_(N-heteroaryl)-W-R_(N-heterocycle), (I)R_(N-heterocycle)-W-R_(N-aryl), (J)R_(N-heterocycle)-W-R_(N-heteroaryl), (K)R_(N-heterocycle)-W-R_(N-heterocycle), and where W is ·(1) —(CH₂)₀₋₄—,·(2) —O—, ·(3) —S(O)O₂—, ·(4) —N(R_(N-5))—, or ·(5) —CO—; (VII)—(CR_(C-x)R_(C-y))₀₋₄-R_(C-aryl where R) _(C-x and Rcy are —H,) C₁-C₄alkyl optionally substituted with one or two —OH, C₁-C₄ alkoxyoptionally substituted with one, two, or three of —F, —(CH₂)₀₋₄—C₃-C₇cycloalkyl, C₂-C₆ alkenyl containing one or two double bonds, C₂-C₆alkynyl containing one or two triple bonds, phenyl, and where R_(C-x)and R_(C-y) are taken together with the carbon to which they areattached to form a carbocycle of three, four, five, six and seven carbonatoms, optionally where one carbon atom is replaced by a heteroatomselected from the group consisting of —O—, —S—, —SO₂—, —NR_(N-2)— andR_(C-aryl) is the same as R_(N-aryl); (VIII)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)-R_(C-aryl), (IX)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-heteroaryl), (X)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)-R_(C-aryl), (XI)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)-R_(C-heteroaryl), (XII)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)-R_(C-heterocycle) and R_(C-heterocycle)is the same as R_(N-heterocycle), (XIII)—(cR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)-R_(C-heterocycle), (XIV)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)-R_(C-aryl),(XV)—(CR_(c-x)R_(C-y))₀₋₄—R_(C-heterocycle)-R_(C-heteroaryl), (XVI)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)-R_(C-heterocycle), (XVII)—[C(R_(C-1)) (R_(C-2))] ₁₋₃—CO—N— (R_(C-3))₂ where R_(C-1) and R_(C-2)are the same or different and are selected from the group consisting of:(A) —H, (B) —C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂ (C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —C—N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,—NR_(1-aR) _(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (C) C₂-C₆ alkenyl with one or two doublebonds, optionally substituted with one, two or three substituentsselected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,—OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁-6 alkyl), —S═O(heteroaryl-C₁₋₆alkyl), —SO₂(C₁₋₆ alkyl), —SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆alkyl), —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (D)—(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of C₁-C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆ alkyl), —S(aryl-C₁₋₆ alkyl),—S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆ alkyl), —S═O(aryl-C₁₋₆ alkyl),—S═O(heteroaryl-C₁₋₆ alkyl), —SO₂ (C₁₋₆ alkyl), —SO₂(aryl-C₁I₆ alkyl),—SO₂(heteroaryl-C₁₋₆ alkyl), —OC—N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1 -heteroaryl)), (E) —(C₁-C₄ alkyl)-R_(C′-aryl) whereR_(C′-aryl) is as defined for R_(1-aryl), (F) —(C₁-C₄alkyl)-R_(C-heteroaryl), (G) —(C₁-C₄ alkyl)-R_(C-hetercycle), (H)—R_(C-heteroaryl), (I) -R_(C-heterocycle), and (J) —R_(C′-aryl), andwhere R_(C-3) is the same or different and is: (A) —H, (B) —C₁-C₆ alkyloptionally substituted with one, two or three substituents selected fromthe group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —S(C₁₋₆alkyl), —S(aryl-C₁₋₆ alkyl), —S(heteroaryl-C₁₋₆ alkyl), —S═O(C₁₋₆alkyl), —S═O(aryl-C₁₋₆ alkyl), —S═O(heteroaryl-C₁₋₆ alkyl), —SO₂ (C₁₋₆alkyl), —SO₂(aryl-C₁₋₆ alkyl), —SO₂(heteroaryl-C₁₋₆ alkyl), —C≡N, —CF₃,C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (C)—(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (D) —(C₁-C₄ alkyl)-R_(C′-aryl), (E) —(C₁-C₄alkyl)-R_(C-heteroaryl), or (F) —(C₁-C₄ alkyl)-R_(C-heterocycle);(XVIII) —(CH₂)_(o)-Q-(CH₂)_(p)-B, where o and p are independentlyintegers of 1-4, Q is O, S, SO, SO₂, NR₁, and B is C₁₋₆ alkyl, aryl,heteroaryl, or heterocycle; (XIX) —O—R₉, —S—R₉, —NH—R₉, or N(R₉)₂;(XXVII) —OC(═O)—R₉ (XXVIII) —C(═O)O—R₉ (XXIX) —N(R₈) C (═O) —R₉ (XXX) —C(═O)N(R₈) —R₉ (XXXI) —SO₂N(R₈)C(═O)—R₉ (XXXII) —C(═O)N(R₈)SO₂—R₉(XXXIII) —SO₂—R₉; wherein R₈ is defined as H or C₁-C₆ alkyl optionallysubstituted with one to three groups independently selected from —OH,—NH₂, —F, —Cl, —Br, and —I; wherein R₉ is defined as (I)—(XVIII) aboveand wherein R₂ is is C₁ to C₆ alkyl , cyclohexyl, cyclopentyl,pyridinyl, phenyl, isoxazole, pyrazole, furan, thiophene, and other fiveand six membered heterocycles containing carbon, nitrogen, oxygen andsulfur, said C₁ to C₆ alkyl, cyclohexyl, cyclopentyl, pyridinyl, phenyl,furan, thiophene may be optionally substituted with one, two or threeradicals selected from CF₃, OCF₃, hydroxyl, halo, C₁₋₂-alkyl,C₁₋₂-haloalkyl, cyano, carboxyl, C₁₋₂-alkoxycarbonyl, C₁₋₂-hydroxyalkyl,thioalkyl, aminosulfonyl, C₁₋₂-alkylaminosulfonyl, methylC₁₋₂-haloalkoxy, amino, C₁₋₂-alkylamino, phenylamino, nitro,C₁₋₂-alkoxy-C₁₋₂-alkyl, C₁₋₂-alkylsulfinyl, C₁₋₂-alkoxy andC₁₋₃-alkylthio.
 2. A compound according to claim 1, wherein at least oneof R₁, R₂ or R₃ is H.
 3. A compound accorind to claim 1, wherein atleast two of R₁, R₂ or R₃ is H.
 4. A compound according to claim 1,wherein R₁ and R₃ are independently: (I) —(CH₂)_(n1)-(R_(1-aryl)), wheren, is zero or one and where R_(1-aryl)is phenyl, 1-naphthyl, 2-naphthyl,indanyl, indenyl, dihydronaphthalyl, or tetralinyl optionallysubstituted with one, two, three, or four of the following substituentson the aryl ring: (A) C₁-C₆ alkyl optionally substituted with one, twoor three substituents selected from the group consisting of C₁-C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (B) C₂-C₆ alkenyl with one or two doublebonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)),C₁-C₃ alkoxy-(R_(1-heteroaryl)), (C) C₂-C₆ alkynyl with one or twotriple bonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —Br, —I, —OH, —SH, —C—N,—CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)),C₁-C₃ alkoxy-(R_(1-heteroaryl)), (D) —F, Cl, —Br, or —I, β(E) —C₁-C₆alkoxy optionally substituted with one, two, or three —F, (F)—NR_(N-2)R_(N-3), where R_(N-2) and R_(N-3) are independently selectedfrom the group consisting of: (1) —H, (2) —C₁-C₆ alkyl optionallysubstituted with one substituent selected from the group consisting of:(a) —OH, and (b) —NH₂, (3) —C₁-C₆ alkyl optionally substituted with oneto three —F, —Cl, —Br, or —I, (4) —C₃-C₇ cycloalkyl, (5) —(C₁-C₂alkyl)-(C₃-C₇ cycloalkyl), (6) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl), (7)—C₂-C₆ alkenyl with one or two double bonds, (8) —C₂-C₆ alkynyl with oneor two triple bonds, (9) —C₁-C₆ alkyl chain with one double bond and onetriple bond, (10) —R_(1-aryl), where R_(1-aryl)is as defined above, and(11) —R_(1-heteroaryl), (G) —OH, (H) —C—N. (I) C₃-C₇ cycloalkyl,optionally substituted with one, two or three substituents selected fromthe group consisting of —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃, —NR1-aR_(1-b), C₁-C₃ alkoxy, C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (K) —CO—(C₁-C₄ alkyl), (L)—SO₂-NR_(1-a)R_(1-b), (M) —CO—NR_(1-a)R_(1-b), or (N) —SO₂— (C₁-C₄alkyl), or (II) —(CH₂)_(n1)-(R_(1-heteroaryl)), where n₁ is zero or oneand where R_(1-heteroaryl) is selected from the group consisting of:pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl,thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl,triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, where theR_(1-heteroaryl) group is bonded to —(CH₂)_(n1)— by any ring atom of theparent R_(1-heteroaryl) group substituted by hydrogen such that the newbond to the R_(1-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is optionally substituted with one, two, three,or four of: (1) C₁-C₆ alkyl optionally substituted with one, two orthree substituents selected from the group consisting of C₁-C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), C₁-C₃ alkoxy, C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (2) C₂-C₆ alkenyl with one or two doublebonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —Br, —I, —OH, —SH, —C—N,—CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), where R_(1-a) and R_(1-b) are—H or C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (3) C₂-C₆ alkynyl with one or two triplebonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), where R_(1-a) and R_(1-b) are—H or C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (4) —F, Cl, —Br, or —I, (5) —C₁-C₆ alkoxyoptionally substituted with one, two, or three —F, (6) —NR_(N-2)R_(N-3),(7) —OH, (8) —C═_N. (9) C₃-C₇ cycloalkyl, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NRIaR_(1-b),where R_(1-a) and Rlb are —H or C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (10) —CO— (C₁-C₄alkyl), (11) —SO₂—NR_(1-a)R_(1-b), (12) —CO—NR_(1-a)R_(1-b), or (13)—SO₂—(C₁-C₄ alkyl), with the proviso that when n₁ is zeroR_(1-heteroaryl) is not bonded to the carbon chain by nitrogen.
 5. Acompound according to claim 1, wherein R₁ and R₃ are independently:phenyl, 1-naphthyl, 2-naphthyl, tetralinyl, indanyl, dihydronaphthyl or6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, each of which is optionallysubstituted with one, two or three of the following substituents whichcan be the same or different and are: (1) C₁-C₆ alkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C═N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (2) —OH, (3) —NO₂, (4) —F, —Cl, —Br, or —I,(5) —CO—OH, (6) —C—N, (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) ₁, (8)—(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), (9) —(CH₂)₀₋₄—CO— (C₂-C₁₂ alkenyl with one,two or three double bonds), (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one,two or three triple bonds), (11) —(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl), (12)—(CH₂)₀₋₄—CO—R_(1-aryl), (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl), (14)—(CH₂)₀₋₄-CO—R_(1-heterocycle), (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4)is selected from the group consisting of morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl,homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyland pyrrolidinyl where each group is optionally substituted with one,two, three, or four of: C₁-C₆ alkyl, (16) —(CH₂)₀₋₄—CO—O—R_(N-5) whereR_(N-5) is selected from the group consisting of: (a) C₁-C₆ alkyl, (b)—(CH₂)₀₋₂-(R_(1-aryl)), (c) C₂-C₆ alkenyl containing one or two doublebonds, (d) C₂-C₆ alkynyl containing one or two triple bonds, (e) C₃-C₇cycloalkyl, and (f) —(CH₂)₀₋₂-(R_(1-heteroaryl)), (17)—(CH₂)₀₋₄-SO₂—NR_(N-2)R_(N-3), (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), (19)—(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl), (20) —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl),(21) —(CH₂)₀₋₄—N(H or R_(N-5)) —CO—O—R_(N-5) where R_(N-5) can be thesame or different, (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, whereR_(N-5) can be the same or different, (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂,where R_(N-5) can be the same or different, (24) —(CH₂)₀₋₄—N(—H orR_(N-5))—CO—R_(N-2) where R_(N-5) and R_(N-2) can be the same ordifferent, (25) —(CH₂)₀₋₄—NR_(N-2)RN₃ where R_(N-2) and R_(N-3) can bethe same or different, (26) —(CH₂)₀₋₄—R_(N-4), (27) —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂ where R_(N-aryl-1)is —H or C₁-C₄ alkyl, (29) —(CH₂)₀₋₄-O—CO—N(R_(N-5))₂, (30)—(CH₂)₀₋₄-O—CS—N(R_(N-5))₂, (31) —(CH₂)₀₋₄—O—(R_(N-5))₂, (32)—(CH₂)₀₋₄—O— (R_(N-5))₂—COOH, (33) —(CH₂)₀₋₄—S—(R_(N-5))₂, (34)—(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with one, two, three,four, or five —F), (35) C₃-C₇ cycloalkyl, (36) C₂-C₆ alkenyl with one ortwo double bonds optionally substituted with C₁-C₃ alkyl, —F, —Cl, —Br,—I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (37) C₂-C₆ alkynylwith one or two triple bonds optionally substituted with C₁-C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, or—NR:L_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (38) —(CH₂)₀₋₄—N(—H or R_(N-5)) —SO₂-R_(N-2)where R_(N-5) and R_(N-2) can be the same or different, or (39)—(CH₂)₀₋₄—C₃-C₇ cycloalkyl.
 6. A compound according to claim 1, whereinR₁ and R₃ are independently R_(N-1)C(O)—; and R_(N-1) isR_(N-heteroaryl) where R_(N-heteroaryl) is selected from the groupconsisting of: pyridinyl, pyrimidinyl, quinolinyl, benzothienyl,indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl,isothiazolyl, naphthyridinyl, cinnolinyl,carbazolyl, beta-carbolinyl,isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,where the R_(N-heteroaryl) group is bonded by any atom of the parentR_(N-heteroaryl) group substituted by hydrogen such that the new bond tothe R_(N-heteroaryl) group replaces the hydrogen atom and its bond,where heteroaryl is optionally substituted with one, two, three, or fourof: (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (2) —OH, (3) —NO₂,(4) —F, —Cl, —Br, or —I (5) —CO—OH, (6) —C—N, (7)—(CH₂)₀₋₄-CO—NR_(N-2)R_(N-3), (8) —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), (9)—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one, two or three double bonds), (10)—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one, two or three triple bonds), (11)—(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl), (12) —(CH₂)₀₋₄-CO—R_(1-aryl), (13)—(CH₂)₀₋₄-COOR_(1-heteroaryl), (14) —(CH₂)₀₋₄-CO—R_(1-heterocycle), (15)—(CH₂)₀₋₄—CO—R_(N-4), (16) —(CH₂)₀₋₄-CO—O—R_(N-5), (17)—(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3), (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), (19)—(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl), (20) —(CH₂)₀₋₄—SO₂— (C₃-C₇ cycloalkyl),(21) —(CH₂)₀₋₄—N(H or R_(N-5)) —CO—O—RN₅ where R_(N-5) can be the sameor different, (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, whereR_(N-5) can be the same or different, (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂,where R_(N-5) can be the same or different, (24) —(CH₂)₀₋₄—N(—H orR_(N-5))—CO—R_(N-2) where R_(N-5) and R_(N-2) can be the same ordifferent, (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) canbe the same or different, (26) —(CH₂)₀₋₄—R_(N-4), (27) —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂ where R_(N-aryl-1)is —H or C₁-C₄ alkyl, (29) —(CH₂)₀₋₄-O—CO—N(R_(N-5))₂, (30)—(CH₂)₀₋₄—O—CS—N(R_(N-5))₂, (31) —(CH₂)₀₋₄—O— (R_(N-5))₂, (32)—(CH₂)₀₋₄—O—(R_(N-5))₂—COOH, (33) —(CH₂)₀₋₄—S—(R_(N-5))₂, (34)—(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with one, two, three,four, or five —F), (35) C₃-C₇ cycloalkyl, (36) C₂-C₆ alkenyl with one ortwo double bonds optionally substituted with C₁-C₃ alkyl, —F, —Cl, —Br,—I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (37) C₂-C₆ alkynylwith one or two triple bonds optionally substituted with C₁-C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂-R_(N-2)where R_(N-5) and R_(N-2) can be the same or different, or (39)—(CH₂)₀₋₄—C₃-C₇ cycloalkyl.
 7. A compound according to claim 1, whereinR₁ and R₃ are independently R_(N-1)C(O)—; and R_(N-1) is phenyl,1-naphthyl, or 2-naphthyl, each of which is optionally substituted withone, two or three of the following substituents which can be the same ordifferent and are: (1) C₁-C₆ alkyl, optionally substituted with one, twoor three substituents selected from the group consisting of C₁-C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (2) —OH, (3) —NO₂, (4) —F, —Cl, —Br, or —I,(5) —CO—OH, (6) —C≡N, (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3), (8)—(CH₂)₀₋₄—CO— (C₁-C₁₂ alkyl), (9) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one,two or three double bonds), (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one,two or three triple bonds), (11) —(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl), (12)—(CH₂)₀₋₄—CO—R_(1-aryl), (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl), (14)—(CH₂)₀₋₄—CO—R_(1-heterocycle), (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4)is selected from the group consisting of morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl,homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyland pyrrolidinyl where each group is optionally substituted with one,two, three, or four of: C₁-C₆ alkyl, (16) —(CH₂)₀₋₄—CO—O—R_(N-5) whereR_(N-5) is selected from the group consisting of: (a) C₁-C₆ alkyl, (b)—(CH₂)₀₋₂—(R_(1-aryl)), (c) C₂-C₆ alkenyl containing one or two doublebonds, (d) C₂-C₆ alkynyl containing one or two triple bonds, (e) C₃-C₇cycloalkyl, and (f) —(CH₂)₀₋₂-(R_(1-heteroaryl)), (17)—(CH₂)₀₋₄-SO₂—NR_(N-2)R_(N-3), (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), (19)—(CH₂)₀₋₄—SO₂— (C₁-C₁₂ alkyl), (20) —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl),(21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can be thesame or different, (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, whereR_(N-5) can be the same or different, (23) —(CH₂) O₄—N—CS—N(R_(N-5))₂,where R_(N-5) can be the same or different, (24) —(CH₂)₀₋₄—N(—H orR_(N-5)) —CO—R_(N-2) where R_(N-5) and R_(N-2) can be the same ordifferent, (25) —(CH₂)₀₋₄-NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) canbe the same or different, (26) —(CH₂)₀₋₄-R_(N-4), (27) —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1)) 2 whereR_(N-aryl-1) is —H or C₁-C₄ alkyl, (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂, (30)—(CH₂)₀₋₄-O—CS—N(R_(N-5))₂, (31) —(CH₂)₀₋₄—O— (R_(N-5))₂, (32)—(CH₂)₀₋₄—O— (R_(N-5))₂—COOH, (33) —(CH₂)₀₋₄—S— (R_(N-5))₂, (34)—(CH₂)₀₋₄—O— (C₁-C₆ alkyl optionally substituted with one, two, three,four, or five —F), (35) C₃-C₇ cycloalkyl, (36) C₂-C₆ alkenyl with one ortwo double bonds optionally substituted with C₁-C₃ alkyl, —F, —Cl, —Br,—I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (37) C₂-C₆ alkynylwith one or two triple bonds optionally substituted with C₁-C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2)where R_(N-5) and R_(N-2) can be the same or different, or (39)—(CH₂)₀₋₄—C₃-C₇ cycloalkyl.
 8. A compound according to claim 1, whereinR₁ and R₃ are independently R_(N-1)C(O)—; and R_(N-1) is phenyloptionally substituted with one, two or three of the followingsubstituents which can be the same or different and are: (1) C₁-C₆alkyl, optionally substituted with one, two or three substituentsselected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,—OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (2) —OH, (3) —NO₂,(4) —F, —Cl, —Br, or —I, (5) —CO—OH, (6) —C—N, (7)—(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3), (8) —(CH₂)₀₋₄—CO— (C₁-C₁₂ alkyl), (9)—(CH₂)₀O₄—CO— (C₂-C₁₂ alkenyl with one, two or three double bonds), (10)—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one, two or three triple bonds), (11)—(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl), (12) —(CH₂)₀-4_CO_R_(1-aryl), (13)—(CH₂)₀₋₄—CO—R_(1-heteroaryl), (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle), (15)—(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from the group consistingof morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide,homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where eachgroup is optionally substituted with one, two, three, or four of: C₁-C₆alkyl, (16) —(CH₂)₀₋₄-CO—O—R_(N-5) where R_(N-5) is selected from thegroup consisting of: (a) C₁-C₆ alkyl, (b) —(CH₂)₀₋₂-(R_(1-aryl)), (c)C₂-C₆ alkenyl containing one or two double bonds, (d) C₂-C₆ alkynylcontaining one or two triple bonds, (e) C₃-C₇ cycloalkyl, and (f)—(CH₂)₀₋₂ (R_(1-heteroaryl)), (17) —(CH₂) O₄—SO₂—NR_(N-2)R_(N-3), (18)—(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), (19) —(CH₂)₀₋₄—SO₂— (C₁-C₁₂ alkyl), (20)—(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl), (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can be the same or different, (22)—(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, where R_(N-5) can be the sameor different, (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) can be thesame or different, (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2) whereR_(N-5) and R_(N-2) can be the same or different, (25)—(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can be the same ordifferent, (26) —(CH₂)₀₋₄—R_(N-4), (27) —(CH₂)₀₋₄-O—CO— (C₁-C₆ alkyl),(28) —(CH₂)₀₋₄—O—P(O)-(OR_(N-aryl-1))₂ where R_(N-aryl-1) is —H or C₁-C₄alkyl, (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂, (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂,(31) —(CH₂)₀₋₄—O— (R_(N-5))₂, (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH, (33)—(CH₂)₀₋₄—S—(R_(N-5))₂, (34) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionallysubstituted with one, two, three, four, or five —F), (35) C₃-C₇cycloalkyl, (36) C₂-C₆ alkenyl with one or two double bonds optionallysubstituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (37) C₂-C₆ alkynyl with one or two triplebonds optionally substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH,—SH, —C—N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (38)—(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5) and R_(N-2) can bethe same or different, or (39) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl.
 9. A compoundaccording to claim 1, wherein R₁ and R₃ are independently RN₋₁C(O)—; andR_(N-1) is phenyl of which is optionally substituted with one, two orthree of the following substituents which can be the same or differentand are: (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-a)ryl), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (2) —OH, (3) —NO₂,(4) —F, —Cl, —Br, or —I, (5) —CO—OH, (6) —C—N, (7)—(CH₂)₀₋₄-CO—NR_(N-2)R_(N-3), (8) —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), (9)—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one, two or three double bonds), (10)—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one, two or three triple bonds), (11)—(CH₂)₀₋₄-CO— (C₃-C₇ cycloalkyl), (12) —(CH₂)₀-4-CO—R_(1-aryl), (13)—(CH₂)₀₋₄—CO—R_(1-heteroaryl), (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle), (15)—(CH₂)₀₋₄-CO—R_(N-4) where R_(N-4) is selected from the group consistingof morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide,homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where eachgroup is optionally substituted with one, two, three, or four of: C₁-C₆alkyl, (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from thegroup consisting of: (a) C₁-C₆ alkyl, (b) —(CH₂)₀₋₂-(R_(1-aryl)), (c)C₂-C₆ alkenyl containing one or two double bonds, (d) C₂-C₆ alkynylcontaining one or two triple bonds, and (e) C₃-C₇ cycloalkyl, (17)—(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can be the same ordifferent, (18) —(CH₂)₀₋₄—N(H or R_(N-5)) —CO—N(R_(N-5))₂, where R_(N-5)can be the same or different, (19) —(CH₂)₀₋₄—N—CS—N(RN₅)₂, where R_(N-5)can be the same or different, (20) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2)where R_(N-5) and R_(N-2) can be the same or different, (21)—(CH₂)₀₋₄-NR_(N-2)RN₃ where R_(N-2) and R_(N-3) can be the same ordifferent, (22) —(CH₂)₀₋₄-R_(N-4), (23) —(CH₂)₀₋₄-O—CO— (C₁-C₆ alkyl),(24) —(CH₂)₀₋₄-O—CO—N(R_(N-5))₂, (25) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂, (26)—(CH₂)₀₋₄-O— (R_(N-5))₂, (27) —(CH₂)₀₋₄—O— (R_(N-5))₂—COOH, (28)—(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with one, two, three,four, or five —F), (29) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) whereR_(N-5) and R_(N-2) can be the same or different, or (30)—(CH₂)₀₋₄—C₃-C₇ cycloalkyl.
 10. A compound according to claim 1, whereinR₁ and R₃ are independently RN-lC(O)—; and R₁ represents —(CH₂)_(n)₁-phenyl where n₁ is zero or one and where phenyl is optionallysubstituted with one, two, or three of the following substituents whichare the same or different: (A) C₁-C₆ alkyl optionally substituted withone, two or three substituents selected from the group consisting ofC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (B) C₂-C₆ alkenyl with one or two doublebonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —Br, —I, —OH, —SH, —C—N,—CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)),C₁-C₃ alkoxy-(R_(1-heteroaryl)), (c) C₂-C₆ alkynyl with one or twotriple bonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —Br, —I, —OH, —SH, —C—N,—CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)),C₁-C₃ alkoxy-(R_(1-heteroaryl)), (D) —F, Cl, —Br, or —I, (E) —C₁-C₆alkoxy optionally substituted with one, two, or three —F, (F)—NR_(N-2)R_(N-3), where R_(N-2) and R_(N-3) are independently selectedfrom the group consisting of: (1) —H, (2) —C₁-C₆ alkyl optionallysubstituted with one substituent selected from the group consisting of:(a) —OH, and (b) —NH₂, (3) —C₁-C₆ alkyl optionally substituted with oneto three —F, —Cl, —Br, or —I, (4) —C₃-C₇ cycloalkyl, (5) —(C₁-C₂alkyl)-(C₃-C₇ cycloalkyl), (6) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl), (7)—C₂-C₆ alkenyl with one or two double bonds, (8) —C₂-C₆ alkynyl with oneor two triple bonds, (9) —C₁-C₆ alkyl chain with one double bond and onetriple bond, (10) —R_(1-aryl), and (11) —R_(1-heteroaryl), (G) —OH, (H)—C—N, (I) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —Br,—I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (J) —CO—(C₁-C₄alkyl), (K) —SO₂—NR_(1-a)R_(1-b), (L) —CO—NR_(1-a)R_(1-b), or (M) —SO₂—(C₁-C₄ alkyl).
 11. A copmpounds according to claim 1, wherein R₁ and R₃are independently phenyl(C₁-C₆)alkyl groups where the phenyl isoptionally substituted with one or two groups independently selectedfrom (A) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), C₁-C₃alkoxy-(R_(1-aryl)), C₁-C₃ alkoxy-(R_(1-heteroaryl)), (B) —F, Cl, —Br,or —I, (C)—C₁-C₆ alkoxy optionally substituted with one, two, or three—F, (D) —NR_(N-2)R_(N-3), where R_(N-2) and R_(N-3) are independentlyselected from the group consisting of: (1) —H, (2) —C₁-C₆ alkyloptionally substituted with one substituent selected from the groupconsisting of: (a) —OH, and (b) —NH₂, (3) —C₁-C₆ alkyl optionallysubstituted with one to three —F, —Cl, —Br, or —I, (4) —C₃-C₇cycloalkyl, (5) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), (6) —(C₁-C₆alkyl)-O—(C₁-C₃ alkyl), (9) —C₁-C₆ alkyl chain with one double bond andone triple bond, (E) —OH, (F) —C_-N. (G) C₃-C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), C₁-C₃ alkoxy-(R_(1-aryl)), C₁-C₃alkoxy-(R_(1-heteroaryl)), (H)—CO—(C₁-C₄ alkyl), (I)—SO₂—NR_(1-a)R_(1-b), where R_(1-a) and R_(1-b) are as defined above, or(J) —CO—NR_(1-a)R_(1-b), where R_(1-a) and R_(1-b) are as defined above.12. A compound according to claim 1, wherein R₁ and R₃ are independentlybenzyl, 4-hydroxybenzyl, 2-fluoro-4-propylbenzyl, 3-amino-4-bromobenzyl;3-chloro-5-methylphenethyl, 3,5-difluorobenzyl, 2-methylphenylpropyl,4-trifluoromethylbenzyl, 4-trifluoromethylphenethyl, 2,3-dichlorobenzyl,and 2-chloro-4-cyanobenzyl.
 13. A compound of the formula:

wherein R₁, R₂ and R₃ are as defined in claim
 1. 14. A compound of theformula:

wherein R₁₁ is —(CH₂)_(n1)-(R_(1-aryl)), or —(CH₂)_(n1)—O— (R_(1-aryl))wherein n1 and R_(1-aryl) are as defined in claim
 1. 15. A compound ofthe formula:


16. A compound of the formula:


17. A compund of the formula:


18. A compound of the formula:


19. A compound of the formula:


20. A compound of the formula:


21. A compound according to Formula II:

or a pharmaceutically acceptable salt or ester thereof, wherein Z is CHor N, and R₁, R₂ and R₃ are defined as follows: R₁ = R₂ = R₃ =

H,


22. A compound of the formula:


23. A compound of the formula:

where R in each compound may independently be R₁ or R₃, wherein Z is CHor N, and wherein R₁, R₂ and R₃ are as defined in claim
 1. 24. Acompound according to claim 1, wherein R₂ is an optionally substitutedfive-membered heterocycle of the formula:


25. A compound according to claim 1, wherein R₂ is an optionallysubstituted six-membered heterocycle of the formula:


26. A compound according to claim 1, wherein R₂ is an optionallysubstituted phenol.
 27. A compound according to claim 1, wherein R₂ isnot a halogenated phenyl, benzyl, aryl or heteroaryl.
 28. A compound ofthe formula:

wherein the imidazole ring, when present is optionally substituted withan aryl or alkyl group.
 29. A compound of the formula:


30. A compound of the formula:

(+/−)-(3R,4R)-4-(3- hydroxyphenyl)piperidin-3-yl1,1′-biphenyl-4-carboxylate hydrochloride

(+/−)-(3R,4R)-4-(4- chlorophenyl)piperidin-3-yl1,1′-biphenyl-4-carboxylate trifluoroacetate

(+/−)-(3R,4R)-4-(4- chlorophenyl)piperidin-3-yl(3,5-difluorophenyl)acetate

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 1-naphthoate hydrochloride

(+/−)-(3R,4R)-4-(4- fluorophenyl)piperidin-3-yl1,1′-biphenyl-4-carboxylate trifluoroacetate

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 4-(trifluoromethoxy)benzoatehydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl 4-iodobenzoate hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl phenoxyacetate hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 4-(trifluoromethyl)benzoatehydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 4-cyanobenzoate hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 3-methylbenzoate trifluoroacetate

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 3-methoxybenzoate trifluoroacetate

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 2-methoxybenzoate hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl benzoate hydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl3′,4′-dimethoxy-1,1′-biphenyl-4-carboxylate hydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl 4-(5-chlorothien-2-yl)benzoatehydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl4′-(trifluoromethyl)-1,1′-biphenyl-4-carboxylate hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 2-methylbenzoate hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 3-(trifluoromethyl)benzoatehydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 4-nitrobenzoate hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 2-naphthoate hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 4-aminobenzoate dihydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl 4-pyridin-4-ylbenzoatedihydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl 4′-(methylthio)-1,1′-biphenyl-4-carboxylate hydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl 3-iodobenzoate hydrochloride

(+/−)-(3R,4R)-4-(3-hydroxyphenyl)piperidin-3-yl benzoate hydrochloride

(+/−)-(3R,4R)-4-(3-hydroxyphenyl)piperidin-3-yl benzoate hydrochloride

(3R,4R)-4-phenylpiperidin-3-yl 1,1′-biphenyl-4-carboxylate

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl 1,1′-biphenyl-3-carboxylatehydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl 4-thien-2-ylbenzoate hydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl4′-(methylsulfonyl)-1,1′-biphenyl-4- carboxylate hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl phenylacetate hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl (3-methoxyphenyl)acetatetrifluoroacetate

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 3,4-dimethoxybenzoatetrifluoroacetate

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl(1R,2S)-2-phenylcyclopropanecarboxylate hydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl3′-chloro-1,1′-biphenyl-4-carboxylate hydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl4′-chloro-1,1′-biphenyl-4-carboxylate hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 1-naphthoate hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 4-phenoxybenzoate hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 3-phenylpropanoate trifluoroacetate

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 2-ethylhexanoate hydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl 4-tert-butylbenzoate hydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl3′-amino-1,1′-biphenyl-4-carboxylate dihydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl 3-(5-chlorothien-2-yl)benzoatehydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl3′-cyano-1,1′-biphenyl-4-carboxylate hydrochloride (Generated byACD/Name software)

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 2,2′-bithiophene-5-carboxylatehydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 5-phenylthiophene-2-carboxylatehydrochloride

(+/−)-(3S,4R)-4-[(1R)-cyclohexa-2,4- dien-1-yl]piperidin-3-yl4-benzoylbenzoate hydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl4′-fluoro-1,1′-biphenyl-4-carboxylate hydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl4′-(trifluoromethoxy)-1,1′-biphenyl-4-carboxylate hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl5-pyridin-2-ylthiophene-2-carboxylate dihydrochloride

(+/−)-(3S,4s)-4-phenylpiperidin-3-yl4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]benzoate hydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl4′-tert-butyl-1,1′-biphenyl-4-carboxylate hydrochloride

(+/−)-(3S,4S)-4-phenylpiperidin-3-yl4′-methoxy-1,1′-biphenyl-4-carboxylate hydrochloride

(+/−)-4′-({[(3S,4S)-4- phenylpiperidin-3-yl]oxy}carbonyl)-1,1′-biphenyl-4-carboxylic acid hydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl 3-(4-methoxyphenyl)propanoatehydrochloride

(+/−)-(3R,4R)-4-phenylpiperidin-3-yl acetate hydrochloride

(+/−)-(3R,4R)-4-pyridin-3- ylpiperidin-3-yl acetate dihydrochloride


31. A compound selected from the group consisting of3-benzyl-5-[(3,5-difluorobenzyl)oxy]piperidine hydrochloride;3-benzyl-5-[(3-methylbenzyl)oxy]piperidine hydrochloride;3-benzyl-5-{[4-(trifluoromethyl)benzyl]oxy}piperidine hydro chloride;3-({5-benzylpiperidin-3-yl]oxy}methyl)benzonitrile;3-benzyl-5-[(3-methoxybenzyl)oxy]piperidine hydrochloride;5-benzylpiperidin-3-yl 1,1′-biphenyl-4-carboxylate trifluoroacetate. 32.A compound selected from the group consisting of3-Benzyloxy-4-furan-3-yl-piperidine-1-carboxylic acid tert-butylester;3-(Biphenyl-4-ylmethoxy)-4-furan-3-yl-piperidine-1-carboxylic acidtert-butylester;4-Furan-3-yl-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylicacid tert-butylester;4-Furan-3-yl-3-(naphthalen-1-ylmethoxy)-piperidine-1-carboxylicacid tert-butylester;4-Furan-3-yl-3-(4-phenoxy-benzyloxy)-piperidine-1-carboxylic acidtert-butylester;3-(4-tert-Butyl-benzyloxy)-4-furan-3-yl-piperidine-1-carboxylicacid tert-butylester;3-(Anthracen-9-ylmethoxy)-4-furan-3-yl-piperidine-1-carboxylicacid tert-butylester;4-Furan-3-yl-3-(3-methyl-benzyloxy)-piperidine-1-carboxylic acidtert-butylester;3-(3,5-Dimethoxy-benzyloxy)-4-furan-3-yl-piperidine-1-carboxylicacid tert-butylester;3-(4-Bromo-benzyloxy)-4-furan-3-yl-piperidine-1-carboxylic acidtert-butylester;4-Furan-3-yl-3-(4-methanesulfonyl-benzyloxy)-piperidine-1-carboxylicacid tert-butylester;4-Furan-3-yl-3-(2-methyl-allyloxy)-piperidine-1-carboxylic acidtert-butylester;3-Cyclohexylmethoxy-4-furan-3-yl-piperidine-1-carboxylic acidtert-butylester;3-(2-Cyclohexyl-ethoxy)-4-furan-3-yl-piperidine-1-carboxylic acidtert-butyl ester;4-Furan-3-yl-3′-isobutoxy-piperidine-1-carboxylic acidtert-butyl ester;3-(2-Ethyl-butoxy)-4-furan-3-yl-piperidine-1-carboxylic acid tert-butylester;3-Benzyloxy-4-furan-3-yl-piperidine;3-(Biphenyl-4-ylmethoxy)-4-furan-3-yl-piperidine;4-Furan-3-yl-3-(naphthalen-2-ylmethoxy)-piperidine;4-Furan-3-yl-3-(naphthalen-1-ylmethoxy)-piperidine;4-Furan-3-yl-3-(4-phenoxy-benzyloxy)-piperidine;3-(4-tert-Butyl-benzyloxy)-4-furan-3-yl-piperidine;3-(Anthracen-9-ylmethoxy)-4-furan-3-yl-piperidine;4-Furan-3-yl-3-(3-methyl-benzyloxy)-piperidine;3-(3,5-Dimethoxy-benzyloxy)-4-furan-3-yl-piperidine;3-(4-Bromo-benzyloxy)-4-furan-3-yl-piperidine;4-Furan-3-yl-3-(2-methyl-allyloxy)-piperidine;3-Cyclohexylmethoxy-4-furan-3-yl-piperidine;3-(2-Cyclohexyl-ethoxy)-4-furan-3-yl-piperidine;4-Furan-3-yl-3-isobutoxy-piperidine;3-(2-Ethyl-butoxy)-4-furan-3-yl-piperidine.33. A compound of the formula:


34. A method for treating a patient who has, or in preventing a patientfrom getting, a disease or condition selected from the group consistingof Alzheimer's disease, for helping prevent or delay the onset ofAlzheimer's disease, for treating patients with mild cognitiveimpairment (MCI) and preventing or delaying the onset of Alzheimer'sdisease in those who would progress from MCI to AD, for treating Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, or diffuse Lewy body type of Alzheimer's disease and whois in need of such treatment, comprising administering to such patient atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or ester thereof, wherein Z, R₁, R₂ andR₃ are as defined in claim
 1. 35. A method for making a compound offormula (I), or a pharmaceutically acceptable salt or ester thereof,wherein Z, R₁, R₂ and R₃ are as defined in claim
 1. 36. A compound ofthe formula:

or a pharmaceutically acceptable salt or ester thereof, wherein Z′ is CHor N; wherein R₃₀ is absent, —OH, or halo; wherein R₄₀ is C₁₋₈ alkyl,C₁₋₈ alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocycl, substituted heterocycl, phenyl, substituted phenyl, C₁₋₈alkyl-phenyl, or C₁₋₈ alkyl-substittued phenyl.
 37. A compound accordingto claim 36, wherein R₃₀ is absent, —OH, or Cl, Br, I or F.
 38. Acompound according to claim 37, wherein R₄₀ is selected from the groupconsisting essentially of —CH₃, —CH₂CH₂-Ph-O—CH₃, -Ph-Ph-CO₂H,-Ph-Ph-OCH₃, -Ph-Ph-C(CH₃)₃, -Ph-Ph-OCF₃, -Ph-Ph-F, -Ph-C(═O)-Ph,-Ph-Ph-CN, -Ph-Ph-NH₂, -Ph-C(CH₃)₃, —CH(CH₂CH₃) (CH₂CH₂CH₂CH₃),—CH₂CH₂Ph, -Ph-O-Ph, naphthalene, -Ph-Ph-Cl, -Ph-(OCH₃)₂, —CH₂-Ph-OCH₃,—CH₂-Ph, -Ph-Ph-S(═O)₂CH₃, -Ph-Ph, pyridyl, Ph, Ph-I, -Ph-Ph-S—CH₃,-Ph-pyridyl, -Ph-NH₂, -Ph-NO₂, -Ph-CF₃, -Ph-CH₃, -Ph-Ph-CF₃,-Ph-Ph-(OCH₃)₂, -Ph-OCH₃, -Ph-CN, —CH₂—O-Ph, -Ph-OCF₃, —CH₂-PhF₂,


39. A compound according to claim 38, wherein Z is CH.
 40. A compoundaccording to claim 39, wherein a single substituent attached to aPh-ring is in the ortho position.
 41. A compound according to claim 39,wherein a single substituent attached to a Ph-ring is in the metaposition.
 42. A compound according to claim 39, wherein a singlesubstituent attached to a Ph-ring is in the para position.
 43. Acompound according to claim 39, wherein di-substituents attached to aPh-ring are in di-meta positions.
 44. A compound according to claim 39,wherein di-substituents attached to a Ph-ring are in a meta and paraposition.
 45. A compound of the formula

wherein R₅₀ is aryl or substituted aryl.
 46. A compound according toclaim 45, wherein R₅₀ is selected form the group consisting of -Ph,-PhBr, -Ph-C(CH₃)₃, -PhF, -PhCl, -PhCN, napthyl, -Ph(CH₃)₂, -Ph-Ph,-PhI, -Ph-OCH₃, -PhCl₂, -Ph-PhCN, and -Ph-(OCH₃)₂.
 47. A compoundaccording to claim 46, wherein a single substituent attached to aPh-ring is in the ortho position.
 48. A compound according to claim 46,wherein a single substituent attached to a Ph-ring is in the metaposition.
 49. A compound according to claim 46, wherein a singlesubstituent attached to a Ph-ring is in the para position.
 50. Acompound according to claim 46, wherein di-substituents attached to aPh-ring are in di-meta positions.
 51. A compound according to claim 46,wherein di-substituents attached to a Ph-ring are in a meta and paraposition.
 52. A compound of the formula

wherein R₆₀ is aryl, substituted aryl, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆cycloalkyl, C₁₋₆ alkyl-C₁₋₆ cycloalkyl; and wherein R₇₀ ist-butoxycarbonyl or H.
 53. A compound according to claim 52, wherein R₆₀is selected from the group consisting of -Ph, -Ph-Ph, napthyl, -Ph-O-Ph,-PhC(CH₃)₃, anthracinyl, -PhCH₃, -Ph(OCH₃)₂, -PhBr, -PhS(═O)₂CH₃,C(═CH₂)CH₃, cyclohexyl, —CH₂-cyclohexyl, —CH(CH₃)₂, and —CH(CH₂CH₃)₂.54. A compound according to claim 53, wherein a single substituentattached to a Ph-ring is in the ortho position.
 55. A compound accordingto claim 53, wherein a single substituent attached to a Ph-ring is inthe meta position.
 56. A compound according to claim 53, wherein asingle substituent attached to a Ph-ring is in the para position.
 57. Acompound according to claim 53, wherein di-substituents attached to aPh-ring are in di-meta positions.
 58. A compound according to claim 53,wherein di-substituents attached to a Ph-ring are in a meta and paraposition.